1,5-benzoxathiepin derivatives, their production and use

ABSTRACT

Novel 1,5-benzoxathiepin derivatives of the formula: ##STR1## [wherein R 1  and R 2  are independently hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy; R 3  and R 4  are independently hydrogen, optionally substituted lower alkyl or optionally substituted cycloalkyl or optionally substituted aralkyl, or both jointly form an optionally substituted ring together with the adjacent nitrogen atom; X is hydrogen, optionally substituted lower alkyl, optionally substituted aryl or a carboxyl group which may be esterified or amidated; Y is ##STR2## (wherein R 5  is hydrogen, acyl or optionally substituted carbamoyl); m is an integer of 0 to 2; n is an integer of 1 to 6] and salts thereof exhibit serotonin S 2  receptor blocking activity, calcium antagonism, actions to relieve cerebral vasospasm and to improve renal circulation and diuretic and antithrombotic activities, and are of value as a prophylactic and therapeutic agent for ischemic cardiopathies, thrombosis, hypertension and cerebral circulatory disorders.

This application is a continuation-in-part application of applicationSer. No. 678,464 filed Dec. 5, 1984, now abandoned.

The present invention relates to novel 1,5-benzoxathiepin derivativeswhich are of value as pharmaceuticals, and to a process for producingthe same.

The present inventors, after intensive research to create a compoundhaving specific serotonin S₂ receptor blocking activity, succeeded inproducing novel 1,5-benzoxathiepin derivatives which exhibit not onlyexcellent serotonin S₂ receptor blocking activity but also calciumantagonism, actions to relieve cerebral vasospasm and to improve renalcirculation and diuretic and antithrombotic activities and are useful asa prophylactic and therapeutic agent for ischemic cardiopathies, such asangina pectoris and myocardial infarction, thrombosis, hypertension andcerebral circulatory disorders, such as cerebral vasospasm and transientischemic attack, and have completed the present invention.

The present invention provides novel compounds of the formula: ##STR3##[wherein R₁ and R₂ are independently hydrogen, halogen, hydroxy, loweralkyl or lower alkoxy; R₃ and R₄ are independently hydrogen, optionallysubstituted lower alkyl or optionally substituted cycloalkyl oroptionally substituted aralkyl, or both jointly form an optionallysubstituted ring together with the adjacent nitrogen atom; X ishydrogen, optionally substituted lower alkyl, optionally substitutedaryl or a carboxyl group which may be esterified or amidated; Y is##STR4## (wherein R₅ is hydrogen, acyl, or optionally substitutedcarbamoyl); m is an integer of 0 to 2; n is an integer of 1 to 6], saltsthereof and a process for producing the same.

Referring to the above formula (I), the halogen represented by R₁ or R₂includes, for example, fluorine, chlorine, bromine and iodine.

The lower alkyl group represented by R₁ or R₂ includes alkyl groupscontaining about 1 to 4 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, sec-butyl and tert-butyl, and the lower alkoxy grouprepresented by R₁ or R₂ includes alkoxy groups containing about 1 to 4carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy and tert-butoxy.

The case that one of R₁ and R₂ is hydrogen and the other is lower alkoxyis preferred and the case that said lower alkoxy group is attached atthe 7th position of the benzoxathiepin moiety is more preferred.

The lower alkyl group represented by R₃ or R₄ includes alkyl groupscontaining about 1 to 4 carbon atoms, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, secbutyl, and tert-butyl.

The said alkyl group may be substituted by, for example, C₃₋₈ cycloalkyl(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl), halogen (e.g., fluorine, chlorine, bromine), hydroxy,lower(C₁₋₄)alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy),lower(C₁₋₅)alkanoyloxy (e.g., acetoxy, propionyloxy, butyryloxy,pivaloyloxy), mono- or di-lower(C₁₋₄)alkylamino (e.g., methylamino,dimethylamino, methylethylamino), C₃₋₈ cycloalkylamino (e.g.,cyclopentylamino, cyclohexylamino), lower(C₁₋₅)alkanoylamino (e.g.,acetamide, propionamide), benzamide, lower(C₁₋₄)alkylthio (e.g.,methylthio, ethylthio, propylthio, butylthio), carbamoyl,N-lower(C₁₋₄)alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl) orN,N-di-lower(C₁₋₄)alkylcarbamoyl (e.g., dimethylcarbamoyl,diethylcarbamoyl, methylethylcarbamoyl).

The cycloalkyl group represented by R₃ or R₄ includes cycloalkyl groupscontaining about 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and the saidcycloalkyl groups may be substituted for example by lower(C₁₋₄)alkyl(e.g., methyl, ethyl, propyl, butyl, etc.), lower(C₁₋₄)alkoxy (e.g.,methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.),lower(C₁₋₅)alkanoylamino (e.g., acetamide, etc.) and hydroxy groups.

The aralkyl group represented by R₃ or R₄ includesphenyl-lower(C₁₋₄)alkyl groups, such as benzyl, phenethyl,3-phenylpropyl, α-methylbenzyl, α-ethylbenzyl, α-methylphenethyl,β-methylphenethyl and β-ethylphenethyl, whereby the phenyl group in thesaid phenyl-lower-alkyl groups may be substituted by 1 to 3substituents, such as halogen (e.g., fluorine, chlorine, bromine,iodine, etc.), lower(C₁₋₄)alkyl groups (e.g., methyl, ethyl, propyl,butyl, etc.), lower(C₁₋₄)alkoxy groups (e.g., methoxy, ethoxy, propoxy,isopropoxy, butoxy, etc.), and methylenedioxy, amino, nitro and hydroxygroups. Examples of such substituted-phenyl-lower alkyl groups include2-(4-chlorophenyl)ethyl, 2-(4-hydroxyphenyl)ethyl,2-(4-methoxyphenyl)ethyl, 2-(3,4-dimethoxyphenyl)ethyl,2-(3,4,5-trimethoxyphenyl)ethyl, 2-(3,4-methylenedioxyphenyl)ethyl,2-(p-tolyl)ethyl, 3,4-dimethoxybenzyl, 3,4-methylenedioxybenzyl,3,4,5-trimethoxybenzyl, 4-ethylbenzyl, 4-chlorobenzyl, etc.

The ring which R₃ and R₄ forms with the adjacent nitrogen atom includescyclic amino groups which may contain, in addition to the said nitrogenatom, hetero atoms, such as nitrogen, oxygen and sulfur, and the cyclicamino groups include 5- to 7-membered cyclic amino groups such aspyrrolidinyl, morpholinyl, piperidyl, piperadinyl and homopiperadinyl.The said cyclic amino groups may have substituents at any substitutivepositions, and such substituents include, for example, lower(C₁₋₄)alkyl,(e.g., methyl, ethyl, propyl, butyl, etc.), aryl, aralkyl, acyl andhetero rings.

The aryl group as the substituent includes, for example, phenyl group,whereby the said phenyl group may be substituted by 1 to 3 substituents,such as halogen (e.g., fluorine, chlorine, bromine, iodine, etc.),lower(C₁₋₄)alkyl groups (e.g., methyl, ethyl, propyl, butyl, etc.),lower(C₁₋₄)alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, etc.), and methylenedioxy, amino, nitro and hydroxy groups. Thearalkyl as the substituent includes, for example,phenyl-lower(C₁₋₄)alkyl such as benzyl and phenethyl,diphenyl-lower(C₁₋₄)alkyl such as benzhydryl andtriphenyl-lower(C₁₋₄)alkyl. The acyl as the substituent includes, forexample, lower(C₁₋₄)fatty acid residues such as lower(C₁₋₄)alkanoyl(e.g., acetyl, propionyl and butyryl) and aromatic organic acid residuessuch as benzoyl and phenyl-lower(C₁₋₄)alkanoyl andphenyl-lower(C₁₋₄)alkenoyl (e.g., cinnamoyl). The phenyl group in thesaid aralkyl groups and aromatic organic acid residues may besubstituted by 1 to 3 substituents, such as halogen (e.g., fluorine,chlorine, bromine, iodine, etc.), lower(C₁₋₄)alkyl groups (e.g., methyl,ethyl, propyl, butyl, etc.), lower(C₁₋₄)alkoxy groups (e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy, etc.), and methylenedioxy, amino,nitro and hydroxy groups. The hetero ring as the substituent includes 5-to 7-membered rings containing 1 to 3 nitrogen atoms, such as pyrrolyl,pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, triazinyl andazepinyl.

As regards R₃ and R₄, is preferred the case that R₃ and R₄ together withthe adjacent nitrogen atom form a ring substituted by aryl, and the casethat R₃ and R₄ together with the adjacent nitrogen atom form piperazinylsubstituted by aryl is more preferred.

The lower alkyl group represented by X includes alkyl groups containingabout 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl and tert-butyl, whereby these groups may besubstituted for example by oxo, hydroxy, acyloxy and aryl. The loweralkyl group substituted by oxo includes, for example,lower(C₁₋₄)alkanoyl, such as acetyl, propionyl and butyryl. The loweralkyl group substituted by hydroxy includes, for example, hydroxymethyl.The acyl group as the acyloxy group includes acyl groups derived fromlower fatty acids, such as lower(C₁₋₅)alkanoyl (e.g., acetyl, propionyland butyryl), and the lower alkyl group substituted by the said acyloxygroup includes, for example, acetyloxymethyl, propionyloxymethyl andbutyryloxymethyl. The lower alkyl group substituted by aryl includes,for example, lower(C₁₋₄)alkyl substituted by phenyl group such asbenzyl, whereby the said phenyl group may be substituted by 1 to 3substituents, such as halogen (e.g., fluorine, chlorine, bromine,iodine, etc.), lower(C₁₋₄)alkyl groups (e.g., methyl, ethyl, propyl,butyl, etc.), lower(C₁₋₄)alkoxy groups (e.g., methoxy, ethoxy, propoxy,isopropoxy, butoxy, etc.), and methylenedioxy, amino, nitro and hydroxygroups.

The aryl group represented by X includes, for example, phenyl groups,whereby the said phenyl group may be substituted by 1 to 3 substituents,such as halogen (e.g., fluorine, chlorine, bromine, iodine, etc.),lower(C₁₋₄)alkyl groups (e.g., methyl, ethyl, propyl, butyl, etc.),lower(C₁₋₄)alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy,butoxy, etc.), and methylenedioxy, amino, nitro and hydroxy groups.

The esterified carboxyl group represented by X includes, for example,lower(C₁₋₄)alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl and tert-butoxycarbonyl, andphenyl-lower(C₁₋₄)alkoxycarbonyl, such as benzyloxycarbonyl.

The amidated carboxyl group represented by X includes, for example,carbamoyl groups, whereby the amino group in the said carbamoyl groupmay be substituted by 1 to 2 substituents, such as lower(C₁₋₄)alkyl,phenyl and phenyl-lower(C₁₋₄)alkyl. As regards X, an esterified carboxylgroup is preferred, and a lower alkoxycarbonyl group is more preferred.

The acyl group represented by R₅ includes, for example, lower alkanoylgroups containing about 1 to 6 carbon atoms, such as acetyl, propionyl,butyryl, valeryl and pivaloyl, and acyl groups derived from aromaticcarboxylic acids, such as phenyl-lower(C₁₋₆)alkanoyl (e.g., benzoyl,phenylacetyl and phenylpropionyl); when the aromatic ring in the saidaromatic carboxylic acid is a phenyl group, said phenyl group may besubstituted by 1 to 3 substituents, such as halogen (e.g., fluorine,chlorine, bromine, iodine, etc.), lower(C₁₋₄)alkyl groups (e.g., methyl,ethyl, propyl, butyl, etc.), lower(C₁₋₄)alkoxy groups (e.g., methoxy,ethoxy, propoxy, isopropoxy, butoxy, etc.), and methylenedioxy, amino,nitro and hydroxy group.

The optionally substituted carbamoyl group represented by R₅ includes,for example, carbamoyl, whereby the amino group in the said carbamoylgroup may be substituted by lower alkyl (e.g., methyl, ethyl, propyl,butyl, etc.), phenyl, phenyl-lower(C₁₋₄)alkyl (e.g., benzyl, phenethyl,etc.), etc. The phenyl group in the said phenyl and phenyl-lower-alkylgroups may be substituted by 1 to 3 substituents, such as halogen (e.g.,fluorine, chlorine, bromine, iodine, etc.), lower(C₁₋₄)alkyl groups(e.g., methyl, ethyl, propyl, butyl, etc.), lower(C₁₋₄)alkoxy groups(e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), andmethylenedioxy, amino, nitro and hydroxy groups. As regards Y, ispreferred a hydroxymethylene group.

The sulfur atom in the formula (I) forms, for example, sulfide,sulfoxide and sulfone, depending upon the value of m. The case that m is0 is preferred.

The group --(CH₂)_(n) -- in the formula (I) forms, for example,methylene, ethylene, trimethylene, tetramethylene, pentamethylene andhexamethylene, depending upon the value of n. Among these groups,trimethylene is preferred.

Salts of the compounds (I) include pharmaceutically acceptable salts,such as salts with inorganic acids being exemplified by hydrochloride,hydrobromide, sulfate, nitrate, phosphate, etc., and salts with organicacids being exemplified by acetate, tartarate, citrate, fumarate,maleate, toluenesulfonate, methanesulfonate, etc.

Preferred compounds (I) are those of the formula: ##STR5## wherein R₆ isphenyl which may be substituted by 1 to 3 members of halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxy, R₂, is C₁₋₄alkoxy and X is C₁₋₄ alkoxycarbonyl, and their pharmaceuticallyacceptable salts.

Other preferred compounds (I) are those of the formula: ##STR6## whereinR_(2') is hydroxy or lower (C₁₋₄) alkoxy, and X is lower (C₁₋₄)alkoxycarbonyl, and their pharmaceutically acceptable salts.

Hydroxy group as the substituent of hydroxyphenylpiperazinyl group maybe attached to any position (i.e. ortho, meta, para) of phenyl group,but preferred is paraposition of phenyl group.

Among the compounds (I"), the compounds of the formula (I") wherein thegroup ##STR7## is 4-(4-hydroxyphenyl)piperazin-1-yl and R_(2') is lower(C₁₋₄) alkoxy are most preferable. Such compounds as those of theformula (I") having hydroxy group as a substituent to phenylpiperazinylgroup have more excellent S₂ receptor blocking activity.

The compound (I) of the present invention can be produced, for example,by subjecting a compound of the formula: ##STR8## [wherein the symbolsare as defined hereinbefore] and a compound (III) of the formula:##STR9## [wherein n, R₃ and R₄ are as defined hereinbefore; W is halogenor a group represented by the formula R--SO₂ --O-- (wherein R islower(C₁₋₄)alkyl, phenyl or p-tolyl)] to a condensation reaction, acondensation reaction and thereafter a reduction reaction, or acondensation reaction and thereafter a reduction reaction, followed byan acylation or carbamoylation reaction.

The said condensation reaction is normally carried out in the presenceof a base. The base includes, for example, inorganic bases, such aspotassium carbonate, potassium hydrogencarbonate, sodium carbonate,sodium methoxide, sodium hydride and lithium diisopropylamide, andorganic amines, such as triethylamine, pyridine and1,8-diazabicyclo[5,4,0]-7-undecene. On this occasion, the reaction canalso be allowed to proceed advantageously, for example, by using sodiumiodide, potassium iodide, etc. as a catalyst. The above reaction can benormally conducted in an organic solvent (e.g., acetone, 2-butanone,acetonitrile, N,N-dimethylformamide, methylene chloride, benzene,toluene, tetrahydrofuran, dioxane, etc.) at a reaction temperature inthe range of -20° C. to +150° C., preferably +20° C. to +120° C.

As a means of reducing the compound (I) wherein Y is ##STR10## asobtained by the condensation reaction, there may be mentioned reactionconditions of reduction with a metal hydride compound, such as lithiumaluminum hydride, lithium borohydride, lithium cyanoborohydride, sodiumborohydride, sodium cyanoborohydride and tri-tert-butoxylithium aluminumhydride; reduction with metallic sodium, metallic magnesium, etc. andalcohols; catalytic reduction using a metal, such as platinum, palladiumand rhodium, or a mixture thereof with an arbitrary support as acatalyst; reduction with a metal, such as iron and zinc, and an acid,such as hydrochloric acid and acetic acid; electrolytic reduction;reduction with a reducing enzyme; reduction with a boron hydridecompound, such as diborane, or a complex compound of a boron hydridecompound and an amine, such as boranetrimethylamine; and so forth. Theabove reaction is normally carried out in the presence of water or anorganic solvent (e.g., methanol, ethanol, ethyl ether, dioxane,methylene chloride, chloroform, benzene, toluene, acetic acid,dimethylformamide, dimethylacetamide, etc.), and the reactiontemperature varies with the reduction means employed, but generally ispreferably in the range of -20° C. to +100° C.

The acylation or carbamoylation reaction subsequent to condensation andreduction can be carried out by use of ordinary means of an acylation orcarbamoylation reaction of alcohol derivatives. The means of suchacylation reaction can be realized, for example, by reacting with areactive derivative (e.g., acid anhydride, acid halide, etc.) of anorganic acid corresponding to R₅ in the presence of an organic amine,such as pyridine, triethylamine and N,N-dimethylaniline, or an inorganicbase, such as sodium carbonate, potassium carbonate and sodiumhydrogencarbonate. The above reaction is normally carried out in anorganic solvent (e.g., methanol, ethanol, ethyl ether, dioxane,methylene chloride, toluene, dimethylformamide, pyridine, etc.), and thereaction temperature generally is preferably in the range of -20° C. to+100° C. The carbamoylation can be realized, for example, by reacting analcohol derivative as obtained in the reduction reaction with anisocyanate derivative (e.g., methyl isocyanate, ethyl isocyanate, phenylisocyanate, p-chlorophenyl isocyanate, etc.) corresponding to R₅. Theabove reaction is normally carried out in an appropriate solvent (e.g.,methanol, ethanol, acetonitrile, dioxane, tetrahydrofuran, methylenechloride, chloroform, toluene, N,N-dimethylformamide, etc.), and thereaction temperature generally is preferably in the range of -20° C. to+150° C.

Also, the compound (I) of the present invention can be obtained, forexample, by reacting a compound of the formula: ##STR11## [wherein W' ishalogen or a group represented by the formula R'--SO₂ --O-- (wherein R'is lower(C₁₋₄)alkyl, phenyl or p-tolyl); other symbols are as definedhereinabove] with an amine derivative of the formula: ##STR12## [whereinR₃ and R₄ are as defined hereinabove]. The reaction of the compound (IV)with the amine derivative (V) can be carried out in an appropriatesolvent (e.g., methanol, ethanol, dioxane, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, methylenechloride, dimethylsulfoxide and an arbitrary solvent mixture thereof).The reaction temperature is preferably in the range of 0° C. to +150°C., and for the purpose of increasing the reaction rate, organic base,such as triethylamine, pyridine and N,N-dimethylaniline, or an inorganicbase, such as potassium carbonate, sodium carbonate and sodiumhydrogencarbonate may be added as a catalyst.

After the said reaction, a compound of the formula (I) wherein Y is##STR13## can be subjected to an acylation or carbamoylation reactionsubsequent to the above-mentioned reduction method or reduction reactionto derive into a compound of the formula (I) wherein Y is ##STR14##

The compound (I) of the present invention can also be produced, forexample, by allowing a compound of the formula: ##STR15## [wherein eachof the symbols is as defined hereinbefore] to undergo condensation withthe compound (V) under reductive conditions.

The said reductive conditions include reaction conditions of catalyticreduction using a metal, such as platinum, palladium, Raney nickel andrhodium, or a mixture thereof with an arbitrary support as a catalyst;reduction with a metal hydride compound, such as lithium aluminumhydride, lithium borohydride, lithium cyanoborohydride, sodiumborohydride and sodium cyanoborohydride; reduction with metallic sodium,metallic magnesium, etc. and alcohols; reduction with a metal, such asiron and zinc, and an acid, such as hydrochloric acid and acetic acid;electrolytic reduction; reduction witha reducing enzyme, and so forth.The above reaction is normally carried out in the presence of water oran organic solvent (e.g., methanol, ethanol, ethyl ether, dioxane,methylene chloride, chloroform, benzene, toluene, acetic acid,dimethylformamide, dimethylsulfoxide, etc.), and the reactiontemperature varies with the means of reduction employed, and generallyis preferably in the range of -20° C. to +100° C. This reaction can beconducted at atmospheric pressure to achieve the desired objectsatisfactorily but may also be carried out under pressure or underreduced pressure according to the circumstances.

Furthermore, the compound (I) of the present invention can be produced,for example, by subjecting a compound of the formula: ##STR16## [whereineach of the symbols is as defined hereinabove] to a reaction of reducingthe amide group. The said reduction reaction can be carried out by useof means of reduction, such as reduction with lithium aluminum hydride,sodium dihydro-bis[2-methoxyethoxy]aluminate, sodium acetoxyborohydride,aluminum hydride, diborane and alkyl borane. The above reaction isnormally carried out in the presence of an organic solvent (e.g., ethylether, tetrahydrofuran, dioxane, toluene, benzene, etc.), and thereaction temperature varies with means of reduction employed, andgenerally is preferably in the range of -20° C. to +120° C. In the caseof a compound of the formula (VII) wherein X is, for example, esterifiedor amidated carboxyl and Y is ##STR17## in the said reduction reaction,these functional groups can be reduced simultaneously, and the desiredamide group alone can also be reduced by protecting the carbonyl groupor by selecting a reducing agent, as the case may be.

A sulfoxide or sulfone compound of the formula (I) wherein m is 1 or 2can also be produced by oxidizing the corresponding sulfide compound.The said oxidation reaction is carried out, for example, by acting anorganic peracid (e.g., m-chloroperbenzoic acid, peracetic acid, etc.) orinorganic acid (e.g., hydrogen peroxide, periodic acid, etc.). The abovereaction is normally carried out in the presence of an organic solvent(e.g., methanol, ethanol, dioxane, dichloromethane, etc.) within thetemperature range of -20° C. to +100° C.

The compound of the formula (I) wherein R₁ or R₂ is hydroxy can beproduced by the above-mentioned reactions, and can also be produced, forexample, by reacting the compound of the formula (IV) wherein R₁ or R₂is a protected hydroxy group (e.g. benzyloxy, methoxymethyloxy) with thecompound (V) in the same manner as described in the above-mentionedreaction of the compounds (IV) and (V), and then subjecting the obtainedcompound of the formula (I) wherein R₁ or R₂ is the protected hydroxygroup to a deprotection reaction.

The deprotection reaction includes catalytic reduction using a metal,such as platinum, palladium or rhodium, or a mixture thereof with anarbitrary support as a catalyst (when the protected hydroxy group isbenzyloxy), and hydrolysis using an inorganic acid, such as hydrochloricacid, sulfuric acid or phosphoric acid or an organic acid, such asformic acid or acetic acid as a catalyst (when the protected hydroxygroup is methoxymethyloxy).

The above catalytic reduction reaction is normally carried out in thepresence of water or an organic solvent (e.g., methanol, ethanol, ethylether, dioxane), and the reaction temperature varies with means ofreduction employed but generally is preferably in the range of -20° C.to +100° C. This reaction can be conducted at atmospheric pressure toachieve the desired object satisfactorily, but may also be carried outunder pressure or under reduced pressure according to the circumstances.

The above hydrolysis reaction is normally carried out in the presence ofwater or an organic solvent (e.g., methanol, ethanol, dioxane,dichloromethane) and ordinarily in the temperature range of -20° C. to+100° C.

The object compound (I) of the present invention thus obtained can beisolated from the reaction mixture by utilizing conventional separationand purification means, for example, means such as extraction,concentration, neutralization, filtration, recrystallization, columnchromatography and thin layer chromatography.

In the case of a compound of the formula (I) wherein Y is ##STR18##there exist at least two stereoisomers. These individual isomers and amixture thereof, naturally, both fall within the scope of the presentinvention, and such isomers can also be produced individually, ifdesired. For example, a single optical isomer of the compound (I) can beobtained by carrying out the above reaction using a single isomer eachof the starting compounds (IV) and (VI). When the product is a mixtureof not less than two kinds of isomers, it can be separated intoindividual isomers by a usual separation technique, for example,separation means such as a method of forming salts with optically activeacids (e.g., camphorsulfonic acid, tartaric acid, dibenzoyltartaricacid, malic acid, etc.), a variety of chromatographic techniques andfractional recrystallization.

The compounds of the present invention, namely the 1,5-benzoxathiepinderivatives represented by the formula (I), exhibit specific serotoninS₂ receptor blocking activity, calcium antagonism, actions to relievecerebral vasospasm and to improve renal circulation, diuretic andantithrombotic activities in animals, in particular, mammals (e.g.,human, pigs, dogs, cats, rabbits, guinea pigs, rats, etc.), and areuseful, for example, as drugs for prevention and treatment of ischemiccardiopathies, such as angina pectoris and myocardial infarction,thrombosis, hypertension and cerebral circulatory disorders, such ascerebral vasospasm and transient ischemic attack. The compounds of thepresent invention are of low toxicity, well absorbed even on oraladministration and highly stable, and when they are used as theabove-mentioned drugs, therefore, they can be safely administered orallyor parenterally, per se or in admixture with suitable, pharmaceuticallyacceptable carriers, excipients or diluents in various pharmaceuticalformulations, such as powders, granules, tablets, capsules andinjectable solutions. While the dosage level varies depending upon theconditions of the diseases to be treated as well as the administrationroute, in the case of administration to human adult for the purpose oftreatment of ischemic cardiopathies or hypertension, for example, thecompounds may be desirably administered orally at a single dose of,normally about 0.1 to 10 mg/kg, preferably about 0.3 to 3 mg/kg, orintravenously at a single dose of about 0.003 to 0.1 mg/kg, preferablyabout 0.01 to 0.1 mg/kg, about once to 3 times daily according to theconditions.

In the case of administration to human adult for the purpose oftreatment of cerebral circulatory disorders, for example, the compoundsmay be desirably administered orally at a single dose of, normally about0.1 to 50 mg/kg, preferably about 0.3 to 30 mg/kg, or intravenously at asingle dose of about 0.003 to 10 mg/kg, preferably about 0.01 to 1mg/kg, about once to 3 times per day according to the conditions.

The starting compounds (II), (IV), (VI) and (VII) can be produced, forexample, by the methods as illustrated in the following reaction schema.##STR19##

In the above reaction schema, Hal is halogen (e.g., bromine, chlorine,etc.); and other symbols are as defined hereinbefore.

In cases in which a compound of the formula (II) wherein X is aryl whichmay be substituted or carboxyl which may be esterified or amidated isproduced, the compound (XII) can be obtained by reacting the compound(VIII) used as a starting compound with the compound (IX) in a suitableorganic solvent (e.g., acetone, acetonitrile, benzene, toluene,methylene chloride, N,N-dimethylformamide, etc.), followed by reactionwith the compound (XI). The said reaction is normally carried outpreferably by allowing a base such as potassium carbonate and sodiumhydrogencarbonate to coexist in the system for the purpose ofaccelerating the reaction rate, and the reaction temperature normally ispreferably in the range of 0° C. to +120° C.

A compound of the formula (XIII) wherein m is 1 or 2 can be produced byoxidizing the compound (XII). The said oxidation reaction is carriedout, for example, by acting an organic peracid (e.g., m-chloroperbenzoicacid, peracetic acid, etc.) or inorganic oxidizing agent (e.g., hydrogenperoxide, periodic acid, etc.). The above reaction is normally conductedin the presence of water or an organic solvent (e.g., methanol, ethanol,dioxane, dichloromethane, etc.) and ordinarily in the temperature rangeof about -20° C. to +100° C. A compound of the formula (XIII) wherein mis 0 can be used in the subsequent reaction without being subjected tothe said oxidation reaction.

The ring-closure reaction to yield the compound (XIV) from the compound(XIII) is normally carried out in an organic solvent (e.g.,N,N-dimethylformamide, acetonitrile, methanol, dimethylsulfoxide, etc.),and is allowed to proceed advantageously in the presence of a base(e.g., sodium methoxide, sodium ethoxide, potassium tert-butoxide,sodium hydride, etc.). The reaction temperature normally is preferablyin the range of -20° to +100° C. In cases in which the compound (XIV) isobtained in the form of an alkali metal salt in the above reaction, sucha compound is neutralized with, for example, acetic acid, hydrochloricacid, sulfuric acid, etc., and the compound (XIV) can be isolated byconventional methods.

In the case of a compound of the formula (II) wherein X is lower alkylwhich may be substituted, the compound (XX) can be obtained by reactingthe compound (VIII) with the compound (XI) to give the compound (XV),then, if necessary, converting the compound (XV) into the compound(XVI), subjecting the compound (XVI) to a ring-closure reaction,followed by alkylation, and subjecting the alkylated compound to areaction of removing the ester group.

The reaction between the compounds (VIII) and (XI) can be carried out inthe same manner as the reaction of the compound (VIII) with the compound(IX). The conversion of the compound (XV) into the compound (XVI) can beconducted in the same manner as the conversion of the compound (XII)into the compound (XIII). The ring-closure reaction of (XVI)→(XVII) canbe carried out in the same manner as the reaction of (XIII)→(XIV).

The reaction between the compounds (XVII) and (XVIII) can be carried outin an appropriate organic solvent (e.g., acetone, 2-butanone,acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, benzene,toluene, tetrahydrofuran, etc.) in the coexistence of a base (e.g.,sodium carbonate, potassium carbonate, sodium hydrogencarbonate, sodiumhydride, sodium methoxide, triethylamine, pyridine, etc.). In such acase, the reaction can be allowed to proceed smoothly by adding aniodine compound, such as potassium iodide and sodium iodide, as acatalyst. The reaction normally is carried out preferably at atemperature in the range of -20° C. to +150° C.

The reaction of (XIX)→(XX) is allowed to proceed by heating the compound(XIX) in an appropriate organic solvent (e.g., dimethylsulfoxide,N,N-dimethylformamide, N,N-dimethylacetamide, etc.) in the coexistenceof a salt (e.g., sodium chloride, lithium chloride, calcium chloride,sodium bromide, etc.) at a temperature in the range of +50° C. to +160°C. in accordance with an ordinary reaction of removing the ester group.

In the case of a compound of the formula (II) wherein X is hydrogen, thecompound (XXI) can be obtained by subjecting the compound (XVII) to thesame reaction as the reaction of (XIX)→(XX).

Also, the compound (XVII) can be produced by reacting the compound(VIII) used as a starting compound with the compound (XXII), thenoxidizing the sulfur atom to give the compound (XXIV), if desired,subjecting it to the same ring-closure reaction as the above-mentionedreaction and further subjecting the resulting compound (XXV) to anordinary hydrolysis reaction.

The reaction between the compounds (XIV) and (XXVII) can be carried outin the same manner as the reaction of the compound (XVII) with thecompound (XVIII). The compound (XXIX) can be obtained by subjecting thecompound (XXVIII) to a reduction reaction. In the said reductionreaction, there may be mentioned reaction conditions of reduction with ametal hydride compound, such as lithium aluminum hydride, lithiumborohydride, lithium cyanoborohydride, sodium borohydride, sodiumcyanoborohydride, and tri-tertbutoxylithium aluminum hydride; reductionwith metallic sodium, metallic magnesium, etc. and alcohols; catalyticreduction using a metal, such as platinum, palladium and rhodium, and amixture thereof with an arbitrary support as a catalyst; reduction witha metal, such as iron and zinc, and an acid, such as hydrochloric acidand acetic acid; electrolytic reduction; reduction with a reducingenzyme; reduction with a boron hydride compound, such as diborane, or acomplex compound of a boron hydride compound and an amine, such asborane-trimethylamine, and so forth. The above reaction is normallycarried out in the presence of water or an organic solvent (e.g.,methanol, ethanol, ethyl ether, dioxane, methylene chloride, chloroform,benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide,etc.), and the reaction temperature varies with means of reductionemployed, and generally is preferably in the range of -20° C. to +100°C.

The reaction of (XXIX)→(XXX) can be carried out using ordinary means ofan acylation or carbamoylation reaction of alcohol derivatives. The saidmeans of an acylation reaction can be realized, for example, by reactinga reactive derivative (e.g., acid anhydride, acid halide, etc.) of anorganic acid corresponding to R₅ with the compound (XXIX) in thepresence of an organic base (e.g., pyridine, triethylamine,N,N-dimethylaniline, etc.).

The above reaction is normally carried out in an organic solvent (e.g.,methanol, ethanol, ethyl ether, dioxane, methylene chloride, toluene,dimethylformamide, pyridine, etc.), and the reaction temperaturegenerally is preferably in the range of -20° C. to +100° C. Thecarbamoylation reaction can be carried out, for example, by reacting analcohol derivative (XXIX) as obtained in the reduction reaction with anisocyanate derivative (e.g., methyl isocyanate, ethyl isocyanate, phenylisocyanate, p-chlorophenyl isocyanate, etc.). The above reaction isnormally conducted in an appropriate organic solvent (e.g., methanol,ethanol, acetonitrile, dioxane, tetrahydrofuran, methylene chloride,chloroform, toluene, N,N-dimethylformamide, etc.), and the reactiontemperature generally is preferably in the range of -20° C. to +150° C.

The reaction of (XIV) with (XXXI) can be carried out in the same manneras the reaction of (XVII) and (XVIII). The compound (XXXIII) can beobtained by hydrolyzing the compound (XXXII) with a dilute mineral acid(e.g., hydrochloric acid, sulfuric acid, etc.). The compound (XXXIV) canbe obtained by subjecting the compound (XXXII) to the same reductionreaction as the reduction reaction of (XXVIII)→(XXIX), and the reactionof (XXXIV)→(XXXV) can be carried out in the same manner as the reactionof (XXIX)→(XXX). The compound (XXXVI) can be obtained by subjecting thecompound (XXXV) to the same reaction as the reaction of(XXXII)→(XXXIII).

The reaction between the compounds (XIV) and (XXXVII) can be carried outin the same manner as the reaction of the compound (XVII) with thecompound (XVIII). The reaction of (XXXVIII)→(XXXIX) can be conducted inthe same manner as the reaction of (XXVIII)→(XXIX), while the reactionof (XXXIX)→(XL) can be carried out in the same manner as the reaction of(XXIX)→(XXX).

The compound of the formula (IV) wherein R₁ or R₂ is a protected hydroxygroup can be produced according to the above-mentioned method forpreparing the compound (IV).

In the above processes for producing the compound (I) and intermediatesthereof, the compounds which are used in the reactions may be used inthe form of salts, such as inorganic acid salts being exemplified byhydrochloride, hydrobromide, sulfate, nitrate and phosphate, etc.,organic acid salts being exemplified by acetate, tartarate, citrate,fumarate, maleate, toluenesulfonate, methanesulfonate, etc., metal saltsbeing exemplified by sodium salt, potassium salt, calcium salt, aluminumsalt, etc., and salts with bases being exemplified by triethylaminesalt, guanidine salt, ammonium salt, hydrazine salt, quinine salt,cinchonine salt, etc., so long as they do not interfere with suchreactions.

The following Reference Examples, Examples, Experiment Examples andPreparation Examples illustrate the present invention in more detail,but they are by no means limitative of the present invention.

REFERENCE EXAMPLE 1

In 350 ml of acetone are dissolved 44.7 g of 2- mercapto-4-methoxyphenoland 88 g of methyl bromoacetate, and 88 g of anhydrous potassiumcarbonate is added to the solution, followed by stirring at roomtemperature for 5 hours and then heating under reflux for 5 hours. Afterthe mixture is cooled, the inorganic substance is filtered off, and thefiltrate is concentrated under reduced pressure. The residue isrecrystallized from ethyl acetatehexane to give 65 g of colorlesscrystals of methyl 4-methoxy-2-methoxycarbonylmethylthiophenoxyacetate,melting point of 78° C.

Elemental analysis, for C₁₃ H₁₆ O₆ S Calcd.: C, 51.99; H, 5.37 Found :C, 52.18; H, 5.37.

REFERENCE EXAMPLE 2

In 300 ml of N,N-dimethylformamide is dissolved 94.4 g of methyl4-methoxy-2-methoxycarbonylmethylthiophenoxyacetate, and 67 g of 28%sodium methoxide is added dropwise to the solution under ice-coolingwith stirring. The reaction mixture is stirred for 1 hour and poured inice-cold water containing dilute hydrochloric acid, and the precipitateis collected by filtration, washed with water, dried and thenrecrystallized from ethyl acetate-hexane to give 58.7 g of colorlesscrystals of methyl7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate, m.p.79°-81° C.

Elemental analysis, for C₁₂ H₁₂ O₅ S Calcd.: C, 53.72; H, 4.51 Found :C, 53.72; H, 4.40.

REFERENCE EXAMPLE 3

In 300 ml of acetone are dissolved 28 g of 2-mercapto-4-methoxyphenoland 25 g of chlorodiethylacetamide, and 25 g of anhydrous potassiumcarbonate is added to the solution, followed by stirring at roomtemperature under a nitrogen gas stream for 3 hours. Then, 28 g ofmethyl bromoacetate and 25 g of anhydrous potassium carbonate are addedto the reaction mixture, followed by heating under reflux for 5 hours.After the mixture is cooled, the inorganic substance is filtered off,and the filtrate is concentrated under reduced pressure. The residue ispurified by column chromatography on silica gel (eluent: hexane:ethylacetate =1:1) to give 45 g of a colorless oily material of methyl2-diethylcarbamoylmethylthio-4-methoxyphenoxyacetate.

Elemental analysis, for C₁₆ H₂₃ NO₅ S Calcd.:C, 56.29; H, 6.79; N, 4.10Found :C, 56.23; H, 6.77; N, 4.18.

REFERENCE EXAMPLE 4

In 160 ml of N,N-dimethylformamide is dissolved 43 g of methyl2-diethylcarbamoylmethylthio-4-methoxyphenoxyacetate, and 30 g of 28%sodium methoxide is added dropwise to the solution under ice-cooling andunder a nitrogen gas stream with stirring, followed by stirring for 6hours. The reaction mixture is poured into ice-cold water containing 15ml of acetic acid, followed by extraction with ethyl acetate. Theorganic layers are combined, washed with water and dried, and thesolvent is evaporated off under reduced pressure. The resulting residueis purified by column chromatography on silica gel (eluent: hexane:ethylacetate =1:1), followed by recrystallization from ethyl acetate to givecolorless prisms of7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-diethylcarboxamide,m.p. 112°-113° C.

Elemental analysis, for C₁₅ H₁₉ NO₄ S Calcd.: C, 58.23; H, 6.19; N, 4.53Found : C, 58.17; H, 6.06; N, 4.54.

REFERENCE EXAMPLE 5

In 600 ml of acetone are dissolved 60 g of 2-mercapto-4-methoxyphenoland 67 g of chloroacetonitrile, and 125 g of anhydrous potassiumcarbonate is added to the solution at room temperature under a nitrogengas stream with stirring, followed by stirring at room temperature for 3hours and then by heating under reflux for 5 hours. After the reactionmixture is cooled, the inorganic substance is filtered off, and thefiltrate is concentrated under reduced pressure. The residue isrecrystallized from ethanol to give colorless prisms of2-cyanomethylthio-4-methoxyphenoxyacetonitrile. Yield of 65 g, m.p. of53°-54° C.

Elemental analysis, for C₁₁ H₁₀ N₂ O₂ S Calcd.: C, 56.39; H, 4.30; N,11.96 Found : C, 56.57; H, 4.32; N, 11.78.

REFERENCE EXAMPLE 6

In 120 ml of N,N-dimethylformamide is dissolved 30 g of2-cyanomethylthio-4-methoxyphenoxyacetonitrile, and 30 g of 28% sodiummethoxide is added dropwise to the solution under ice-cooling and undera nitrogen gas stream with stirring, followed by stirring for 2 hours.The reaction mixture is poured in ice-cold water containing 12 g ofacetic acid, and the precipitate is collected by filtration, washed withwater and recrystallized from chloroform to give colorless prisms of3-amino-7-methoxy-2H-1,5-benzoxathiepin-4-carbonitrile. Yield of 19.5 g,m.p. of 203°-205° C.

REFERENCE EXAMPLE 7

In 60 ml of ethanol is suspended 6.0 g of3-amino-7-methoxy-2H-1,5-benzoxathiepin-4-carbonitrile, and 18 ml ofconcentrated hydrochloric acid is added to the suspension, followed bystirring at 80 to 90° C. for 30 minutes. After the reaction mixture iscooled, ammonium chloride, which separates out, is filtered off, and thefiltrate is concentrated under reduced pressure. The residue isrecrystallized from ethyl acetate-hexane to give colorless prisms of7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carbonitrile. Yieldof 5.1 g, m.p. of 132°-133° C.

Elemental analysis, for C₁₁ H₉ NO₃ S Calcd.: C, 56.16; H, 3.86; N, 5.95Found : C, 56.08; H, 3.79; N, 5.85.

REFERENCE EXAMPLE 8

In 200 ml of methanol is dissolved 15 g of7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carbonitrile, andthe solution is saturated with dried hydrogen chloride, followed byallowing the solution to stand at room temperature for 4 days. 10 ml ofwater is added to the reaction solution, the mixture is allowed to standovernight and concentrated under reduced pressure. The residue ispurified by column chromatography on silica gel (eluent; chloroform) togive 6.0 g of methyl7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate asobtained in Reference Example 2, together with 6.0 g of the startingmaterial being recovered.

REFERENCE EXAMPLE 9

A mixture of 2.0 g of methyl7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate, 1.96 gof 1-chloroacetyl 4-phenylpiperazine, 0.6 g of potassium iodide, 1.24 gof anhydrous potassium carbonate and 30 ml of methyl ethyl ketone isheated under reflux for 30 minutes with stirring. The inorganicsubstance is filtered off, and the filtrate is concentrated underreduced pressure. The resulting residue is dissolved in ethyl acetate,and the solution is washed with water and dried, followed byconcentration by evaporation of the solvent under reduced pressure. Theresidue is purified by column chromatography on silica gel (eluent:hexane:ethyl acetate =2:1→1:1), followed by recrystallization from ethylacetate-hexane to give 2.1 g of colorless crystals of methyl7-methoxy-3-oxo-4-[2-oxo-2-(4-phenylpiperazin-1-yl)-ethyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate,m.p. of 146°-148° C.

IR spectrum (KBr) cm⁻¹ : 1740, 1640

NMR spectrum (CDCl₃) δ: 4.78 ppm(2H, double doublet, C_(4--CH) ₂ CO--)

Elemental analysis, for C₂₄ H₂₆ N₂ O₆ S Calcd.: C, 61.26; H, 5.57; N,5.95 Found : C, 61.40; H, 5.60; N, 5.90.

REFERENCE EXAMPLES 10 to 19

By the same procedure as described in Reference Example 9, methyl3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate derivatives areallowed to undergo condensation with halides to give the compounds asshown in Table 1.

                  TABLE 1    ______________________________________     ##STR20##    Refer-    ence    Exam-    ple                               Melting    No.   R.sub.1 R.sub.2                   X'                 point (°C.)    ______________________________________    10    7-CH.sub.3 O                    ##STR21##         109-110    11    7-CH.sub.3 O                   CH.sub.2 CON(C.sub.2 H.sub.5).sub.2                                      Oily material    12    7-CH.sub.3 O                   (CH.sub.2).sub.3Br Oily material    13    7-CH.sub.3 O                   (CH.sub.2).sub.4Br Oily material    14    7-CH.sub.3 O                   (CH.sub.2).sub.5Br Oily material    15    7-CH.sub.3 O                   (CH.sub.2).sub.6Br Oily material    16    7-CH.sub.3 O                    ##STR22##         Oily material    17    7-CH.sub.3 O                   CH.sub.3           Oily material    18    7-CH.sub. 3 O                   CH.sub.2 CO.sub.2 CH.sub.3                                      Oily material    19    7-CH.sub.3 O                    ##STR23##         78-81    ______________________________________

REFERENCE EXAMPLE 20

In 15 ml of methanol is suspended 1.0 g of methyl4-diethylcarbamoylmethyl-7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateas obtained in Reference Example 11, and 0.2 g of sodium borohydride isadded portionwise to the suspension under ice-cooling with stirring.When the spot corresponding to the starting compounds disappears on theTLC chromatogram, the reaction mixture is concentrated under reducedpressure, and water is added to the residue, followed by extraction withethyl acetate. The organic layers are combined, washed with water anddried, and the solvent is evaporated off under reduced pressure. Theresulting residue is separated and purified by column chromatography onsilica gel (eluent:hexane-ethyl acetate =1:1), and from the first eluateis obtained 0.117 g of colorless needles of methyltrans-4-diethylcarbamoylmethyl-3-hydroxy-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate,m.p. of 120°-123° C. (recrystallized from ethyl acetate-n-hexane).

Elemental analysis, for C₁₈ H₂₅ NO₆ S Calcd.: C, 56.38; H, 6.57; N, 3.65Found : C, 56.50; H, 6.73; N, 3.61.

From the subsequent eluate, there is obtained 0.587 g of methylcis-4-diethylcarbamoylmethyl-3-hydroxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.Recrystallization from ethyl acetate-n-hexane yields colorless prisms,m.p. of 120°-122° C.

Elemental analysis, for C₁₈ H₂₅ NO₆ S Calcd.: C, 56.38; H, 6.57; N, 3.65Found : C, 56.54; H, 6.71; N, 3.65.

REFERENCE EXAMPLE 21

By the same procedure as described in Reference Example 20, the compoundas obtained in Reference Example 9 is subjected to reduction reactionwith sodium borohydride to give two kinds of isomers, methyl cis- andtrans-3-hydroxy-7-methoxy-4-[2-oxo-2-(4-phenylpiperazin-1-yl)-ethyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.Cis isomer: Recrystallization from ethyl acetate yields colorlessneedles, m.p. of 213°-215° C. Mass spectrum m/e: 472 (M⁺),

Elemental analysis, for C₂₄ H₂₈ N₂ O₆ S Calcd.: C, 61.00; H, 5.97; N,5.93 Found : C, 60.87; H, 5.84; N, 5.86.

Hydrochloride of transisomer: Recrystallization from methanol-etheryields colorless needles, m.p. of 170°-180° C. (decomp.)

Elemental analysis, for C₂₄ H₂₈ N₂ O₆ S.Hcl.1/2H₂ O Calcd.: C, 55.64; H,5.83; N, 5.40 Found : C, 55.38; H, 5.73; N, 5.44.

REFERENCE EXAMPLE 22

A 2.0 g quantity of methyl4-(1,3-dioxolan-2-yl)-ethyl-7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateas obtained in Reference Example 10, together with 2.0 g of lithiumchloride, 0.3 ml of water and 20 ml of dimethylsulfoxide, is stirred at100° C. for 5 hours. After the mixture is cooled, water is added to it,followed by extraction with ethyl acetate. The organic layers arecombined, washed with water and dried, and the solvent is evaporatedoff. The resulting residue is purified by column chromatography onsilica gel (eluent: hexane-ethyl acetate =2:1) to give a colorless oilymaterial of4-(1,3-dioxolan-2-yl)-ethyl-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-one.

IR spectrum (neat) cm⁻¹ : 1730

NMR spectrum (CDCl₃) δ: 1.6-2.3(4H, multiplet), 3.70 ppm (3H, singlet,OCH₃), 3.7-4.2(4H, multiplet), 4.60(2H, doublet), 4.6-5.0(2H,multiplet).

Mass spectrum m/e: 310 (M⁺)

REFERENCE EXAMPLE 23

By the same procedure as described in Reference Example 1, methyl2-methoxycarbonylmethylthiophenoxyacetate is obtained from2-mercaptophenol and methyl bromoacetate. Recrystallization fromhexane-ethyl acetate yields colorless prisms, m.p. of 65°-66° C.

Elemental analysis, for C₁₂ H₁₄ O₅ S Calcd.: C, 53.32; H, 5.22 Found :C, 53.20; H, 5.29.

REFERENCE EXAMPLE 24

Methyl 2-methoxycarbonylmethylthiophenoxyacetate as obtained inReference Example 23 is treated in the same manner as described inReference Example 2 to give a colorless oily material of methyl3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.

Elemental analysis, for C₁₁ H₁₀ O₄ S Calcd.: C, 55.45; H, 4.23 Found :C, 55.33; H, 4.41.

REFERENCE EXAMPLE 25

A mixture of 30 g of methyl7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate, 50 g of1-bromo-3-chloropropane, 46 g of anhydrous potassium carbonate, 10 g ofpotassium iodide, 1.0 g of tetrabutyl ammonium iodide and 300 ml ofacetonitrile is heated under reflux for 4 hours. After the mixture iscooled, the inorganic substance is filtered off, and the filtrate isconcentrated under reduced pressure. The resulting residue is dissolvedin ethyl acetate, and the solution is washed with water and dried. Thesolvent is evaporated off under reduced pressure, and the residue ispurified by column chromatography on silica gel (eluent:hexane:ethylacetate:methylene chloride =10:1:10). Recrystallization from ethanolyields colorless prisms of methyl4-(3-chloropropyl)-7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.Yield of 17 g. m.p. of 64°-65° C.

Elemental analysis, for C₁₅ H₁₇ ClO₅ S Calcd.: C, 52.25; H, 4.97 Found :C, 52.33; H, 5.10.

REFERENCE EXAMPLE 26

In 200 ml of tetrahydrofuran is dissolved 17 g of methyl4-(3-chloropropyl)-7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate,and 2.8 g of borane trimethylamine complex and 12 g of boron trifluorideetherate are added to the solution, followed by stirring at roomtemperature for 20 hours. The reaction solution is concentrated underreduced pressure, and ice-cold water and dilute hydrochloric acid areadded to the residue, followed by extraction with ethyl acetate. Theorganic layer is washed with water and dried, and the solvent isevaporated off under reduced pressure. The resulting residue is purifiedby column chromatography on silia gel (eluent: hexane:ethyl acetate=1:1) to give 13 g of a colorless oily material of methylcis-4-(3-chloropropyl)-3-hydroxy-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.

Elemental analysis, for C₁₅ H₁₉ ClO₅ S Calcd.: C, 51.95; H, 5.52 Found :C, 52.08; H, 5.48.

Mass spectrum m/e: 346, 348(M⁺)

REFERENCE EXAMPLE 27

2-Mercapto-4-methylphenol is treated with methyl bromoacetate in thesame manner as described in Reference Example 1 to give methyl2-methoxycarbonylmethylthio-4-methylphenoxyacetate as colorless prisms(recrystallized from methanol). mp. 45°-46° C.

Elemental Analysis for C₁₃ H₁₆ O₅ S Calcd.: C, 54.92; H, 5.67 Found : C,55.10; H, 5.70.

REFERENCE EXAMPLE 28

4-Chloro-2-mercaptophenol is treated with methyl bromoacetate in thesame manner as described in Reference Example 1 to give methyl4-chloro-2-methoxycarbonylmethylthiophenoxyacetate as colorless prisms(recrystallized from ethyl acetate-hexane). mp. 76°-77° C.

Elemental Analysis for C₁₂ H₁₃ ClO₅ S Calcd.: C, 47.30; H, 4.30 Found :C, 47.40; H, 4.29.

REFERENCE EXAMPLE 29

Methyl 2-methoxycarbonylmethylthio-4-methylphenoxyacetate (8.9 g) istreated with sodium methoxide in the same manner as described inReference Example 2 to give methyl7-methyl-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate (5.8 g)as a colorless oil.

Mass spectrum (m/e): 252(M⁺).

IR ν_(max) ^(neat) cm⁻¹ : 1730-1750(C=O)

NMR (CDCl₃) δ: 2.22(3H,s,C₇ --CH₃), 3.80(3H,s,COOCH₃), 4.62(2H,doubledoublet, C₂ --H), 4.80(1H,s,C₄ --H).

REFERENCE EXAMPLE 30

Methyl 4-chloro-2-methoxycarbonylmethylthiophenoxyacetate is treatedwith sodium methoxide in the same manner as described in ReferenceExample 2 to give methyl7-chloro-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate ascolorless needles, mp. 92°-94° C.

Elemental Analysis for C₁₁ H₉ ClO₄ S Calcd.: C, 48.45; H, 3.33 Found :C, 48.45; H, 3.06.

REFERENCE EXAMPLE 31

Methyl 7-methyl-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate(4.1 g) is treated with 1-bromo-3-chloropropane in the same manner asdescribed in Reference Example 25 to give methyl4-(3-chloropropyl)-7-methyl-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate(2.0 g) as a colorless oil.

Mass spectrum (m/e): 328, 330(M⁺).

IR ν_(max) ^(neat) cm⁻¹ : 1760, 1730(C=O)

NMR (CDCl₃) δ: 2.20(3H,s,C₇ --CH₃), 3.70(3H,s,CO₂ CH₃), 4.62(2H, doubledoublet, C₂ --H).

REFERENCE EXAMPLE 32

Methyl4-(3-chloropropyl)-7-methyl-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate2.0 g is reduced by sodium borohydride in the same manner as describedin Reference Example 20 to give Methyl cis- and trans-4-(3-chloropropyl)-3-hydroxy-7-methyl-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.

cis-isomer (1.2 g, colorless oil)

IR ν_(max) ^(neat) cm⁻¹ : 3520(OH), 1730(C=O).

NMR (CDCl₃) δ: 2.28ppm(3H,s,C₇ --CH₃) 3.78ppm(3H,s,CO₂ CH₃)

trans-isomer (0.7 g, colorless oil)

IR ν_(max) ^(neat) cm⁻¹ : 3540(OH), 1720(C=O)

NMR (CDCl₃) δ: 2.24ppm(3H,s,C₇ --CH₃) 3.55ppm(3H,s,CO₂ CH₃).

REFERENCE EXAMPLE 33

Methyl 7-chloro-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate istreated with 1-bromo-3-chloropropane in the same manner as described inReference Example 25 to give methyl7-chloro-4-(3-chloropropyl)-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateas a colorless oil.

IR ν_(max) ^(neat) cm⁻¹ : 1760, 1730(C=O)

NMR (CDCl₃) δ: 3.68ppm(3H,s,CO₂ CH₃) 4.62ppm(2H, double doublet, C₂--H).

REFERENCE EXAMPLE 34

Methyl7-chloro-4-(3-chloropropyl)-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateis reduced by sodium borohydride in the same manner as described inReference Example 20 to give methyl cis- and trans-7-chloro-4-(3-chloropropyl)-3-hydroxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.

cis-isomer (colorless oil)

IR ν_(max) ^(neat) cm⁻¹ : 3520(OH), 1730(C=O)

NMR (CDCl₃) δ: 3.80ppm(3H,s,CO₂ CH₃).

trans-isomer (colorless oil)

IR ν_(max) ^(neat) cm⁻¹ : 3520(OH), 1720(C=O)

NMR (CDCl₃) δ: 3.60ppm(3H,s,CO₂ CH₃).

REFERENCE EXAMPLE 35

A mixture of methyl4-(3-chloropropyl)-7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate(5.0 g) obtained in Reference Example 25, dimethylsulfoxide (30 ml),water (0.3 ml) and lithium chloride (1.5 g) is heated at 100° C. for 5hours with stirring. The reaction mixture is poured into ice-water andextracted with ethyl acetate. The organic layer is washed with water,dried over anhydrous sodium sulfate and evaporated to dryness in vacuo.The residue is submited to column chromatography on silica gel elutingwith hexane-ethyl acetate (2:1) to give4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-one(2.0 g) as a colorless oil.

Elemental Analysis for C₁₃ H₁₅ ClO₃ S Calcd.: C, 54.45; H, 5.27 Found :C, 54.60; H, 5.24.

Mass spectrum (m/e): 286, 288(M⁺).

REFERENCE EXAMPLE 36

To a solution of4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-one(0.8 g) in tetrahydrofuran (2 ml) and methanol (10 ml) is added sodiumborohydride (0.1 g) under ice-cooling. The reaction mixture is stirredfor another one hour and evaporated in vacuo. The residue is mixed withethyl acetate and water. The orgonic layer is separated, washed withwater, dried over anhydrous sodium sulfate and evaporated to dryness invacuo. The residue is submited to column chromatography on silica geleluting with ethyl acetate-hexane (1:1) to give4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol(0.68 g) as a colorless oil.

Elemental Analysis for C₁₃ H₁₇ ClO₃ S Calcd.: C, 54.03; H, 5.93 Found :C, 54.37; H, 6.13.

REFERENCE EXAMPLE 37

To a solution of methylcis-4-[3-chloropropyl)-3-hydroxy-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate(3.5 g) in methanol (50 ml) is added a solution of lN NaOH (10 ml) andstirred for 15 hours. The reaction mixture is evaporated in vacuo. Afteraddition of water 50 ml to the residue, the mixture is washed with ethylether. The aqueous layer is acidified with dil.HCl solution andextracted with ethyl acetate. The organic layer is washed with water,dried over anhydrous Na₂ SO₄ and evaporated to dryness in vacuo. Theresidue is recrystallized from hexane-AcOEt to give cis-4-(3-chloropropyl)-3-hydroxy-7-methoxy-3,4-dihydro-2H-1,5-benzoaxathiepin-4carboxylicacid (2.1 g) as colorless prisms, mp. 175°-178° C.

Elemental Analysis for C₁₄ H₁₇ O₅ SCl Calcd.: C, 50.53; H, 5.15 Found:C, 50.69; H, 5.07.

REFERENCE EXAMPLE 38

To a solution ofcis-4-(3-chloropropyl)-3-hydroxy-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylicacid (1.0 g) in pyridine (5 ml) is added acetic anhydride (4 ml), andallowed to stand at room temperature for 5 hours. The reaction mixtureis poured into water and extracted with ethyl acetate. The organic layeris washed with water, dried over anhydrous Na₂ SO₄ and evaporated todryness in vacuo. The residue is recrystallized from AcOEthexane to givecis-3-acetoxy-4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylicacid (0.95 g) as colorless prisms, mp 163°-165° C.

Elemental Analysis for C₁₆ H₁₉ O₆ SCl Calcd.: C, 51.27; H, 5.11 Found:C, 51.44; H, 5.17.

REFERENCE EXAMPLE 39

To a mixture ofcis-3-acetoxy-4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-1.5-benzoxathiepin-4-carboxylicacid (0.8 g), benzylamine (0.27 g) and N,N-dimethylformamide (6 ml) isadded diethyl phosphorocyanidate (0.52 g) and then triethylamine (0.45g) under ice-cooling with stirring. The reaction mixture is stirredunder ice-cooling for 10 minutes and at room temperature for further 3hours and then poured into ice-water. The crystalline deposit iscollected by filtration, washed with water, and then with ethyl acetateand dried to givecis-3-acetoxy-4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-N-benzylcarboxamide(0.57 g) which is isolated as colorless plates, mp 224°-226° C. (fromethyl acetate).

Mass spectrum m/e: 463, 465(M⁺)

Elemental Analysis for C₂₃ H₂₆ NO₅ SCl Calcd.: C, 59.54; H, 5.65; N,3.02 Found : C, 59.81; H, 5.48; N, 2.82.

REFERENCE EXAMPLE 40

2-Mercapto-5-methoxyphenol is treated in the same manner as described inReference Example 1 to give methyl5-methoxy-2-methoxycarbonylmethylthiophenoxyacetate as a colorless oil.

Mass spectrum (m/e): 300(M⁺)

IR spectrum ν_(max) ^(neat) cm⁻¹ : 1740 (ester)

REFERENCE EXAMPLE 41

Methyl 5-methoxy-2-methoxycarbonylmethylthiophenoxyacetate is treated inthe same manner as described in Reference Example 2 to give methyl8-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate as apale yellow oil.

Mass spectrum (m/e): 268(M⁺)

NMR spectrum (CDCl₃) δ: 3.72(3H, singlet), 3.78(3H, singlet), 4.76(2H,double doublet, J=18Hz), 4.80(lH, singlet).

REFERENCE EXAMPLE 42

Methyl 8-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateis treated in the same manner as described in Reference Example 25 togive methyl4-(3-chloropropyl)-3-oxo-8-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateas a colorless oil .

Mass spectrum (m/e): 344, 346(M⁺)

IR spectrum ν_(max) ^(neat) cm⁻¹ : 1755, 1720

REFERENCE EXAMPLE 43

Methyl4-(3-chloropropyl)-3-oxo-8-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateis treated with sodium borohydride in the same manner as described inReference Example 20 to give methyl cis- andtrans-3-hydroxy-4-(3-chloropropyl)-8-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.cis-Isomer (colorless oil):

Mass spectrum (m/e): 346, 348(M⁺)

IR spectrum ν_(max) ^(neat) cm⁻¹ : 3520(OH), 1735(C=O)

trans-Isomer (colorless oil):

Mass spectrum (m/e): 346, 348(M⁺)

IR spectrum ν_(max) ^(neat) cm⁻¹ : 3500(OH), 1720(C=O).

REFERENCE EXAMPLE 44

4-Benzyloxy-2-mercaptophenol is treated in the same manner as describedin Reference Example 1 to give methyl4-benzyloxy-2-methoxycarbonylmethylthiophenoxyacetate as colorlessprisms.

Melting point: 52°-53° C.

Elemental Analysis for C₁₉ H₂₀ O₆ S Calcd.: C, 60.63; H, 5.36 Found : C,60.75; H, 5.39.

REFERENCE EXAMPLE 45

Methyl 4-benzyloxy-2-methoxycarbonylmethylthiophenoxyacetate is treatedin the same manner as describe in Reference Example 2 to give methyl7-benzyloxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate ascolorless prisms. Melting point: 101°-102° C.

Elemental Analysis for C₁₈ H₁₆ O₅ S Calcd. C, 62.78; H, 4.68 Found : C,62.71; H, 4.38.

REFERENCE EXAMPLE 46

Methyl 7-benzyloxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateis treated in the same manner as described in Reference Example 25 togive methyl7-benzyloxy-4-(3-chloropropyl)-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateas a colorless oil.

IR spectrum ν_(max) ^(neat) cm⁻¹ : 1755, 1725

NMR spectrum (CDCl₃) δ: 3.72(3H, singlet), 4.60 (2H, double doublet).

REFERENCE EXAMPLE 47

Methyl7-benzyloxy-4-(3-chloropropyl)-3-oxo-3,4-dihydro-2H,1,5-benzoxathiepin-4-carboxylateis treated in the same manner as described in Reference Example 20 togive methylcis-7-benzyloxy-4-(3-chloropropyl)-3-hydroxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateas a colorless oil.

IR spectrum ν_(max) ^(neat) cm⁻¹ : 3550(OH), 1740(ester).

REFERENCE EXAMPLE 48

Methyl7-benzyloxy-4-(3-chloropropyl)-3-hydroxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateis treated in the same manner as described in the below-mentionedExample 39 to give methylcis-7-benzyloxy-3-hydroxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylatedihydrochloride as an amorphous powder.

Elemental Analysis for C₃₁ H₃₆ N₂ O₅ S.2HCl Calcd.: C, 59.90; H, 6.16;N, 4.51 Found : C, 59.87; H, 6.32; N, 4.63.

REFERENCE EXAMPLE 49

A mixture of 3.0 g of methylcis-7-benzyloxy-4-(3-chloropropyl)-3-hydroxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate,1.9 g of N-4-hydroxyphenylpiperazine and 5 ml of N,N-dimethylacetamideis stirred at 90° C. for 6 hours. Water is added to the mixture and themixture is extracted with ethyl acetate. The organic layers arecombined, washed with water and dried and the solvent is evaporated offunder reduced pressure. The residue is purified by silica gel columnchromatography [eluent: haxane-ethyl acetate-methanol (70:150:6)]to give2.3 g of methylcis-7-benzyloxy-3-hydroxy-4-[3-[4-(4-hydroxyphenyl)piperazin-1-yl]propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateas a pale yellow oil. The product is converted to a powder of thehydrochloride.

Elemental Analysis for C₃₁ H₃₆ N₂ O₆ S.HCl Calcd.: C, 61.93; H, 6.20; N,4.66 Found : C, 61.91; H, 6.01; N, 4.65.

EXAMPLE 1

A mixture of 10 g of methyl7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate, 9.8 gof 3-(4-phenylpiperazin-1-yl)propyl chloride, 6.2 g of anhydrouspotassium carbonate, 3.0 g of potassium iodide and 150 ml of methylethyl ketone is stirred with heating under reflux for 25 hours. Afterthe mixture is cooled, the inorganic substance is filtered off, and thefiltrate is concentrated under reduced pressure. The resulting residueis dissolved in ethyl acetate, and the solution is washed with water anddried. The solvent is evaporated off under reduced pressure, and theresulting residue is purified by column chromatography on silica gel(eluent: hexane:ethyl acetate =3:1) to give methyl7-methoxy-3-oxo-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.Recrystallization from methanol gives white crystals. m.p. of 110°-112°C. Yield of 2.1 g.

Elemental analysis, for C₂₅ H₃₀ N₂ O₅ S Calcd.: C, 63.81; H, 6.43; N,5.95 Found : C, 63.50; H, 6.37; N, 5.71.

EXAMPLES 2 to 3

By the same procedure as described in Example 1, the compounds as shownin Table 2 are obtained by the reaction of methyl7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate with analkyl halide.

                                      TABLE 2    __________________________________________________________________________     ##STR24##                               Elemental analysis (hydrochloride)                               (Parenthesized figures are    Example                    calculated values)    No.  R.sub.1, R.sub.2              X'               C     H    N    __________________________________________________________________________    2    7-CH.sub.3 O               ##STR25##       White powder as 3/4 hydrate. 60.206.302.57                               (60.10)(6.50)(2.70)    3    7-CH.sub.3 O               ##STR26##       White powder as 11/2 hydrate 56.036.342.84                               (56.25)(6.25)(2.90)    __________________________________________________________________________

EXAMPLE 4

A mixture of 1.7 g of methyl4-(4-bromobutyl)-7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateas obtained in Reference Example 13, 1.37 g of N-phenylpiperazine, 0.7 gof potassium iodide, 1.2 g of anhydrous potassium carbonate and 30 ml ofacetonitrile is stirred with heating under reflux for 1.5 hours. Afterthe mixture is cooled, the inorganic substance is filtered off, and thefiltrate is concentrated under reduced pressure. Water is added to theresidue, and the mixture is extracted with ethyl acetate. The organiclayers are combined, washed with water and dried, and the solvent isevaporated off under reduced pressure. The residue is purified by columnchromatography on silica gel (eluent: hexane-ethyl acetate =2:1) to give1.0 g of a colorless oily material of methyl7-methoxy-3-oxo-4-[4-(4-phenylpiperazin-1-yl)butyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.Hydrochloride, white crystals, m.p. of 155°-165° C. (decomp).

Elemental analysis, for C₂₆ H₃₂ N₂ O₅ S.2HCl.1/2H₂ O Calcd.: C, 55.12;H, 6.22; N, 4.95 Found : C, 55.30; H, 6.19; N, 4.96.

EXAMPLES 5 to 11

By the same procedure as described in Example 4, the compounds as shownin Table 3 are obtained by the substitution reaction of the halidesobtained in Reference Examples 12 to 15 with amines.

                                      TABLE 3    __________________________________________________________________________     ##STR27##                                 Hydrochloride                                         Elemental Analysis for hydro-                                 Melting chloride (parenthesized                                                        Massres    Ex.                          Point   are calculated values)                                                        spectrum    No.       R.sub.1, R.sub.2            X'                   (°C.)                                         C    H    N    m/e    __________________________________________________________________________    5  7-CH.sub.3 O             ##STR28##           130-150 (decomp.)                                         2 HCl.1/2 H.sub.2 O 56.006.414.81                                         (55.85)(6.42)(4.83)    6  7-CH.sub.3 O             ##STR29##           powder  2 HCl 57.266.704.74 (57.42)(6.54)(4.7                                         9)    7  7-CH.sub.3 O             ##STR30##           oil (free base)        560(M.sup.+)    8  7-CH.sub.3 O             ##STR31##           oil (free base)        504,506 (M.sup.+)    9  7-CH.sub.3 O             ##STR32##           oil (free base)        500(M.sup.+)    10 7-CH.sub.3 O             ##STR33##           oil (free base)        471(M.sup.+)    11 7-CH.sub.3 O             ##STR34##           oil (free base)        503(M.sup.+)    __________________________________________________________________________

EXAMPLE 12

In a solvent mixture of 40 ml of tetrahydrofuran and 200 ml of methanolis dissolved 38 g of methyl7-methoxy-3-oxo-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate as obtained in Example 1, and 3.7 g ofsodium borohydride is added portionwise to the solution underice-cooling with stirring. After the completion of reaction, the solventis evaporated off under reduced pressure, and water is added to theresidue, followed by extraction with ethyl acetate. The organic layersare combined, washed with water and dried, and the solvent is evaporatedoff under reduced pressure. The resulting residue is separated andpurified by column chromatography on silica gel (eluent: hexane-ethylacetatemethanol =20:10:1). From the first eluate there is obtained 12 gof a colorless oily material of methyltrans-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.

IR spectrum (neat) cm⁻¹ : 3520, 1720

NMR spectrum (CDCl₃) δ: 3.45(3H, singlet, OCH₃), 3.60(3H, singlet, OCH3)

The compound turns into a white powder as the hydrochloride salt.

Elemental analysis, for C₂₅ H₃₂ N₂ O₅ S.2HCl.1/2H₂ O Calcd.: C, 54.15;H, 6.36; N, 5.05 Found : C, 54.27; H, 6.20; N, 4.89.

From the subsequent eluate, there is obtained 18 g of a colorless oilymaterial of methylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.

IR spectrum (neat) cm⁻¹ : 3530, 1740

NMR spectrum (CDCl₃) δ: 3.60(3H, singlet, OCH₃), 3.62 (3H, singlet,OCH₃)

As the hydrochloride salt, m.p. of 165°-175° C. (decomp.)

Elemental analysis, for C₂₅ H₃₂ N₂ O₅ S.2HCl.1/2H₂ O Calcd.: C, 54.15;H, 6.36; N, 5.05 Found : C, 54.02; H, 6.33; N, 5.00.

EXAMPLES 13 to 22

By the same procedure as described in Example 12, the compounds asobtained in Examples 2 to 11 are subjected to reduction reaction withsodium borohydride to give the compounds as shown in Table 4.

                                      TABLE 4    __________________________________________________________________________     ##STR35##    Configuration shows relationship between OH (3rd position) and CO.sub.2    CH.sub.3 (4th position)                                                    Elemental Analysis for                                                    hydro-                                            Hydrochloride                                                    chloride (parenthesized                                                    figures                                            Melting are calculated values)    Ex. No.         R.sub.1, R.sub.2               X'                   configuration                                            Point (°C.)                                                    C    H    N    __________________________________________________________________________    13   7-OCH.sub.3                ##STR36##           cis + trans                                             Powder  (60.39)(6.82)(2.71)60.476                                                    .892.64C.sub.26 H.sub.33                                                    NO.sub.5 S.HCl.1/2                                                    H.sub.2 O    14   7-OCH.sub.3                ##STR37##           cis + trans                                             Powder  (57.37)(6.59)(2.91)57.446                                                    .692.71C.sub.23 H.sub.29                                                    NO.sub.5 S.HCl.3/4                                                    H.sub.2 O    15a  7-OCH.sub.3                ##STR38##           cis      Powder  (55.36)(6.52)(4.97)55.306                                                    .414.94C.sub.26 H.sub.34                                                    N.sub.2 O.sub.5 S.2HCl.1/4                                                     H.sub.2 O    15b  7-OCH.sub.3                ##STR39##           trans    Carbonate 128-130                                                     (59.10)(6.61)(5.11)58.976                                                    .755.28C.sub.26 H.sub.34                                                    N.sub.2 O.sub.5 S.H.sub.2                                                    CO.sub.3    16   7-OCH.sub.3                ##STR40##           cis      Powder  (54.49)(6.95)(4.85)54.816                                                    .814.73C.sub.27 H.sub.36                                                    N.sub.2 O.sub.5 S.2HCl.H.s                                                    ub.2 O    17   7-OCH.sub.3                ##STR41##           cis + trans                                             165-175 free base )( 112-114                                                     (65.34)(7.44)(5.44)65.237                                                    .545.27C.sub.28 H.sub.38                                                    N.sub.2 O.sub.5 S (free                                                    base)    18a  7-OCH.sub.3                ##STR42##           cis      free base )( 133-135                                                     (68.30)(6.81)(4.98)68.486                                                    .734.97C.sub.32 H.sub.38                                                    N.sub.2 O.sub.5 S (free                                                    base)    18b  7-OCH.sub.3                ##STR43##           trans    free base )( 173-176                                                     (68.30)(6.81)(4.98)68.346                                                    .814.82C.sub.32 H.sub.38                                                    N.sub.2 O.sub.5 S (free                                                    base)    19a  7-CH.sub.3 O                ##STR44##           cis      140-150                                                     (50.59)(5.85)(4.72)50.646                                                    .114.61C.sub.25 H.sub.31                                                    N.sub.2 O.sub.5 SCl.2HCl.3                                                    /4 H.sub.2 O    19b  7-CH.sub.3 O                ##STR45##           trans    free base )( 112-113                                                     (59.22)(6.16)(5.52)59.286                                                    .275.34 C.sub.25 H.sub.31                                                    N.sub.2 O.sub.5 SCl (free                                                    base)    20a  7-CH.sub.3 O                ##STR46##           cis      Powder  (51.83)(6.52)(4.65)51.996                                                    .554.39C.sub.26 H.sub.34                                                    N.sub.2 O.sub.6 S.2HCl.11/                                                    2 H.sub.2 O    20b  7-CH.sub.3 O                ##STR47##           trans    Powder  (52.61)(6.45)(4.72)52.516                                                    .624.83C.sub.26 H.sub.34                                                    N.sub.2 O.sub.6 S.2HCl.H.s                                                    ub.2 O    21a  7-CH.sub.3 O                ##STR48##           cis      Powder  (49.86)(6.36) (7.26)49.97                                                    .667.06C.sub.24 H.sub.31                                                    N.sub.3 O.sub.5 S.2HCl.7/4                                                     H.sub.2 O    21b  7-CH.sub.3 O                ##STR49##           trans    Powder  (51.89)(6.20)(7.56)51.755                                                    .977.54C.sub.24 H.sub.31                                                    N.sub.3 O.sub.5 S.2HCl.1/2                                                     H.sub.2 O    22   7-CH.sub.3 O                ##STR50##           cis + trans                                             Powder  (55.76)(6.84)(2.50)56.016                                                    .822.30C.sub.26 H.sub.35                                                    NO.sub.7 S.HCl.H.sub.2    __________________________________________________________________________                                                    O

EXAMPLE 23

To a tetrahydrofuran solution of sodium monoacetoxyborohydride preparedby suspending 0.1 g of sodium borohydride in 15 ml of tetrahydrofuranand by adding 0.19 g of acetic acid dropwise to the suspension withstirring is added 0.5 g of methylcis-3-hydroxy-7-methoxy-4-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateas obtained in Reference Example 21, followed by heating under refluxfor 20 hours. The reaction solution is concentrated under reducedpressure, and water is added to the residue, followed by extraction withethyl acetate. The organic layer is washed with water and dried, and thesolvent is evaporated off under reduced pressure. The residue ispurified by silica-gel column chromatography (eluent: hexane-ethylacetate=1:1) to give 0.2 g of a colorless oily material of methylcis-3-hydroxy-7-methoxy-4-[2-(4-phenylpiperazin-1-yl)ethyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate,which turns into a white powder as the hydrochloride salt.

Elemental analysis, for C₂₄ H₃₀ N₂ O₅ S.2HCl.1/4H₂ O Calcd.: C, 53.77;H, 6.11; N, 5.23 Found : C, 53.67; H, 6.19; N, 5.35.

EXAMPLE 24

To a mixture of 0.24 g of lithium aluminum hydride and 50 ml of ethylether is added 0.7 g of methylcis-3-hydroxy-7-methoxy-4-[2-oxo-2-(4-phenylpiperazin-1-yl)-ethyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateas obtained in Reference Example 21, followed by heating under refluxfor 2 hours. After the reaction mixture is cooled, 0.25 ml of water,0.25 ml of a 15% aqueous sodium hydroxide solution and 0.75 ml of waterare added to it in the mentioned order, followed by stirring for 30minutes. The precipitate is filtered off and washed with ethyl acetate,and the filtrate and washings are combined and concentrated underreduced pressure. The residue is recrystallized from ethyl acetate togive 0.5 g of colorless prisms ofcis-4-hydroxymethyl-7-methoxy-4-[2-(4-phenylpiperazin-1-yl)ethyl]-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol,m.p. of 153°-156° C.

Elemental analysis, for C₂₃ H₃₀ N₂ O₄ S Calcd.: C, 64.16; H, 7.02; N,6.51 Found : C, 64.30; H, 7.10; N, 6.48.

EXAMPLE 25

Methylcis-4-diethylcarbamoylmethyl-3-hydroxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateas obtained in Reference Example 20 is treated in the same manner asdescribed in Example 24 to give a colorless oily material ofcis-4-(2-diethylaminoethyl)-4-hydroxymethyl-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol.

IR spectrum (neat) cm⁻¹ : 3400

NMR spectrum (CDCl₃) δ: 1.00 ppm(6H, triplet, 2CH₃), 1.75(2H, m),2.45(6H, m), 3.58(3H, singlet, OCH₃), 3.60(2H, double doublet, CH₂ OH),3.90(2H, singlet, ##STR51##

EXAMPLE 26

In 20 ml of methanol is dissolved 0.8 g of4-(1,3-dioxaolan-1-yl)ethyl-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-oneas obtained in Reference Example 22, and sodium borohydride is addedportionwise to the solution with stirring. At the time when the spotcorresponding to the starting compound disappears on the thin-layerchromatogram, a solution of 1 N aqueous sodium hydroxide is added to thereaction solution, followed by extraction with ethyl acetate. Theorganic layers are combined, washed with water and dried, and thesolvent is evaporated off under reduced pressure. 5 ml of dioxane, 2 mlof water and 40 mg of p-toluenesulfonic acid are added to the residue,and the mixture is stirred at room temperature for 8 hours. Water isadded to the reaction solution, followed by extraction with ethylacetate. The organic layers are combined, and the solvent is evaporatedoff under reduced pressure. 10 ml of acetonitrile and 400 ml of4-phenylpiperazine are added to the residue thus obtained, followed bystirring at room temperature for 20 hours. 200 mg of sodiumcyanoborohydride and 5 ml of methanol are added to the mixture, followedby stirring for further 10 hours. Sodium hydroxide (1 N) is added to thereaction solution, followed by extraction with ethyl acetate. Theorganic layers are combined, washed with water and dried, and thesolvent is evaporated off under reduced pressure. The resulting residueis separated and purified by silica-gel column chromatography (eluenthexane:ethyl acetate-methanol=10:10:1) to give 200 mg of a colorlessoily material of7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol,which turns into a white powder as the hydrochloride salt.

Elemental analysis, for C₂₃ H₃₀ N₂ O₃ S.2HCl.1/2H₂ O Calcd.: C, 55.63;H, 6.70; N, 5.64 Found : C, 55.73; H, 6.61; N, 5.64.

EXAMPLE 27

In 10 ml of pyridine is dissolved 0.7 g ofcis-4-(2-diethylaminoethyl)-4-hydroxymethyl-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-olas obtained in Example 25, and 6 ml of acetic anhydride is added to thesolution, followed by allowing the mixture to stand at room temperaturefor 3 hours. The reaction solution is poured into ice-cold water,followed by extraction with ethyl acetate. The organic layer is washedwith an aqueous sodium hydrogencarbonate solution and watersuccessively, and dried, and the solvent is evaporated off under reducedpressure to give 0.66 g of a colorless oily material ofcis-3-acetoxy-4-acetoxymethyl-7-methoxy-4-(2-diethylamino-ethyl)-3,4-dihydro-2H-1,5-benzoxathiepin. The hydrochloride salt, whenrecrystallized from ethanol-ethyl ether, turns into white crystals.,m.p. of 177°-179° C.

Elemental analysis, for C₂₁ H₃₁ NO₆ S.HCl.1/5H₂ O Calcd.: C, 54.19; H,7.01; N, 3.06 Found : C, 54.27; H, 7.05; N, 3.06.

EXAMPLE 28

By the same procedure as described in Example 27, the compound asobtained in Example 12 is acetylated to give methylcis-3-acetoxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate,which, when recrystallized from ethyl acetate-n-hexane, turns intocolorless prisms, m.p. of 168°-170° C. The structure of this product canbe determined by an X-ray analysis of crystals.

Elemental analysis, for C₂₇ H₃₅ N₂ O₆ S Calcd.: C, 63.01; H, 6.66; N,5.44 Found : C, 63.01; H, 6.69; N, 5.40.

EXAMPLE 29

By the same procedure as described in Example 24, the compound asobtained in Example 12 is reduced with lithium aluminum hydride to givecis-4-hydroxymethyl-7-methoxy-4-3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol.Recrystallization from ethyl acetate yields colorless needles, m.p. of163°-165° C.

Elemental analysis, for C₂₄ H₃₂ N₂ O₄ S Calcd.: C, 64.84; H, 7.25; N,6.30 Found : C, 64.76; H, 7.31; N, 6.39.

EXAMPLE 30

In 5 ml of methanol is dissolved 160 mg of methylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateas obtained in Example 12, and 3 ml of 1 N sodium hydroxide is added tothe solution, followed by stirring at 60° C. for 1 hour. The reactionsolution is concentrated under reduced pressure, and 5 ml of water isadded to the residue. The mixture is adjusted to pH 3 to 4 with 1 Nhydrochloric acid and cooled, and the precipitate is collected byfiltration, washed with acetone and dried to give 0.13 g of whitecrystals ofcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylicacid, m.p. of 250°-260° C.(decomp.).

Elemental analysis, for C₂₄ H₃₀ N₂ O₅ S.H₂ O Calcd.: C, 60.48; H, 6.77;N, 5.88 Found: C, 60.27; H, 6.73; N, 5.66.

EXAMPLE 31

In 5 ml of N,N-dimethylformamide is dissolved 0.3 g of methylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate,and 0.08 g of phenyl isocyanate and 0.1 ml of triethylamine are added tothe solution, followed by stirring at room temperature for 3 hours. Thereaction solution is poured into water, followed by extraction withethyl acetate. The organic layer is washed with water, dried andconcentrated under reduced pressure, and the residue is chromatographedon a column of silica gel. The fractions which are eluted with a mixtureof n-hexane:ethyl acetate=3:1 to 1:1 are collected and concentratedunder reduced pressure to give 0.4 g of a colorless oily material ofmethylcis-7-methoxy-3-phenylcarbamoyloxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.Addition of hydrochloric acidethanol solution yields 0.3 g of thehydrochloride salt in the form of a powder.

Elemental analysis, for C₃₂ H₃₇ N₃ O₆ S.2HCl.1/2H₂ O Calcd.: C, 57.05;H, 5.99; N, 6.23 Found : C, 56.78; H, 5.96; N, 6.37.

EXAMPLE 32

By the same procedure as described in Example 1, methyl3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate as obtained inReference Example 24 is allowed to undergo condensation with3-(4-phenylpiperazin-1-yl)propyl chloride, and methyl3-oxo-[3-(4-phenylpiperazin-1-yl)-propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateis isolated as the hydrochloride salt. Recrystallization from methanolproduces white crystals, m.p. of 176°-178° C.

Elemental analysis, for C₂₄ H₂₈ N₂ O₄ S.HCl.1/2H₂ O Calcd.: C, 59.67; H,6.26; N, 5.80 Found : C, 59.49; H, 6.33; N, 5.79.

EXAMPLE 33

By the same procedure as described in Example 12, methyl3-oxo-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylatehydrochloride is reduced with sodium borohydride, and separation andpurification is effected by silica-gel column chromatography (eluent:hexane-ethyl acetate-methanol=10:10:1). The trans and cis derivativesare obtained from the first and second eluates, respectively.

Methylcis-3-hydroxy-4-[3-(4-phenylpiperazin-1-yl)-propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylatedihydrochloride. Recrystallization from methanol-ethyl acetate yieldscolorless plates, m.p. of 196°-198° C.

Elemental analysis, for C₂₄ H₃₀ N₂ O₄ S.2HCl Calcd.: C, 55.92; H, 6.26;N, 5.43 Found : C, 55.73; H, 6.15; N, 5.51.

Methyltrans-3-hydroxy-4-[3-(4-phenylpiperazin-1-yl)-propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylatedihydrochloride.

White powder (amorphous powder).

Elemental analysis, for C₂₄ H₃₀ N₂ O₄ S.2HCl.1/3H₂ O Calcd.: C, 55.28;H, 6.31; N, 5.37 Found : C, 55.29; H, 6.49; N, 5.11.

EXAMPLE 34

In 3 ml of ethanol is dissolved 0.12 g ofcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylicacid as obtained in Example 30, and 50 mg of diethyl sulfate and 100 mgof sodium hydrogencarbonate are added to the solution, followed byheating under reflux for 3 hours. The reaction solution is poured inwater, followed by extraction with ethyl acetate. The organic layer iswashed with water and dried, and the solvent is evaporated off underreduced pressure. The resulting residue is purified by columnchromatography on silica gel (eluent: hexane-ethyl acetate=1:1) to give50 mg of a colorless oily material of ethylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)-propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate,which turns into a white powder (amorphous powder) as the hydrochloridesalt.

Elemental ayalysis, for C₂₆ H₃₄ N₂ O₅ S.2HCl.1/4H₂ O Calcd.: C, 55.36;H, 6.52; N, 4.97 Found : C, 55.30; H, 6.64; N, 4.94.

EXAMPLES 35 to 36

By the same procedure as described in Example 4, the compounds as shownin Table 5 are obtained from the compounds as obtained in ReferenceExample 12.

                                      TABLE 5    __________________________________________________________________________     ##STR52##                                             Elemental analysis for                                             hydrochloride (parenthesized                                             figures are calculated                                                            Mass spec-    Ex. No.         R.sub.1,R.sub.2               X'                  Melting point °C.                                             C    H    N    trum    __________________________________________________________________________                                                            m/e                                             C.sub.26 H.sub.32 N.sub.2                                             O.sub.6 S.1/2H.sub.2 O    35   7-CH.sub.3 O                ##STR53##          Free base 133-135                                             .sub. 60.95 (61.27)                                                  .sub. 6.30 (6.53)                                                       .sub. 5.48 (5.50)                                                            500 (M.sup.+)    36   7-CH.sub.3 O                ##STR54##          Oily material            484    __________________________________________________________________________                                                            (M.sup.+)

EXAMPLES 37 to 38

By the same procedure as described in Example 12, the compounds ofExamples 35 and 36 are reduced to give the compounds as shown in Table6.

                                      TABLE 6    __________________________________________________________________________     ##STR55##                                                    Elemental analysis for                                                    hydrochloride                                                    (parenthesized                                          Hydrochloride                                                    figures are calculated                                                    values)    Ex. No.         R.sub.1,R.sub.2              X'                   Configuration                                          Melting point, °C.                                                    C    H    N    __________________________________________________________________________                                                    C.sub.26 H.sub.34 N.sub.2                                                    O.sub.6 S.2HCl    37a  7-CH.sub.3 O               ##STR56##           cis    Powder    .sub. 54.56 (54.26)                                                         .sub. 6.29 (6.30)                                                              .sub. 5.05                                                              (4.87)                                                    C.sub.26 H.sub.34 N.sub.2                                                    O.sub.6 S.2HCl.1/2H.sub.2                                                    O    37b  7-CH.sub.3 O               ##STR57##           trans  Powder    .sub. 53.67 (53.42)                                                         .sub. 6.34 (6.38)                                                              .sub. 4.68                                                              (4.79)                                                    C.sub.26 H.sub.34 N.sub.2                                                    O.sub.5 S.2HCl.H.sub.2 O    38a  7-CH.sub.3 O               ##STR58##           cis    Powder    .sub. 54.07 (54.07)                                                         .sub. 6.61 (6.63)                                                              .sub. 4.76                                                              (4.85)                                                    C.sub.26 H.sub.34 N.sub.2                                                    O.sub.5 S.2HCl.3/4H.sub.2                                                    O    38b  7-CH.sub.3 O               ##STR59##           trans  Powder     .sub. 54.40 (54.49)                                                         .sub. 6.41 (6.60)                                                              .sub. 4.84                                                              (4.89)    __________________________________________________________________________

EXAMPLE 39

A 14 g quantity of methylcis-4-(3-chloropropyl)-3-hydroxy-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateas obtained in Reference Example 26, together with 9.0 g of4-phenylpiperazine, 9.0 g of anhydrous potassium carbonate, 0.5 g ofpotassium iodide and 100 ml of acetonitrile, is heated under reflux for20 hours. After the mixture is cooled, the inorganic substance isfiltered off, and the filtrate is concentrated under reduced pressure.The residue is dissolved in ethyl acetate, and the organic layer iswashed with water and dried. After the solvent is evaporated off underreduced pressure, the residue is purified by column chromatography onsilica gel (eluent: hexane:ethyl acetate:methanol=10:10:1), and theresulting oily material is crystallized as the hydrochloride salt togive colorless crystals of methylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylatedihydrochloride, which is identical with the compound as obtained inExample 12. Yield of 8 g.

The product is recrystallized from 50% ethanol to give colorless prismsof methylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.monohydrochloride.

m.p. 154°-155° C. (determined on a micro melting point apparatus(Yanagimoto) 132° C. (decomp.) (determined by the method described inThe Pharmacopoeia of Japan)

Elemental analysis, for C₂₅ H₃₂ N₂ O₅ S.HCl.2H₂ O Calcd.: C, 55.09; H,6.84; N, 5.14 Found : C, 55.46; H, 6.77; N, 5.09.

IR ν_(max) ^(KBr) cm⁻¹ : 3600-3300, 1735, 1720, 1600, 1480, 1250

NMR (d₆ -DMSO)δ: 1.3-1.8 ppm(2H), 2.7-3.8 ppm (12H), 3.68 ppm (3H,singlet), 3.75 ppm (3H, singlet), 3.8-4.3 ppm (3H), 6.7-7.4 ppm (8H).

EXAMPLES 40 to 48

By the same procedure as described in Example 39, the compounds as shownin Table 7 are obtained by the substitution reaction of methylcis-4-(3-chloropropyl)-3-hydroxy-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylatewith various amines.

                                      TABLE 7    __________________________________________________________________________     ##STR60##                                  Elemental analysis for hydrochloride                         Hydrochloride                                  (parenthesized figures are calculated                                  values)    Ex. No.              Melting point, °C.                                  C      H      N    __________________________________________________________________________                                  C.sub.26 H.sub.33 NO.sub.5 S.HCl.1/2H.sub.2                                  O    40          ##STR61##      Powder   .sub. 60.14 (60.39)                                         .sub. 6.69 (6.82)                                                .sub. 2.67 (2.71)                                  C.sub.26 H.sub.35 NO.sub.7 S..HCl.1/2H.sub.2                                   O    41          ##STR62##      Powder   .sub. 56.68 (56.67)                                         .sub. 6.97 (6.77)                                                .sub.  2.51 (2.54)                                  C.sub.27 H.sub.32 FNO.sub.6 S.HCl.1/2H.sub.2                                   O    42          ##STR63##      Powder   .sub. 57.38 (57.59)                                         .sub. 5.80 (5.73)                                                .sub. 2.40 (2.49)                                  C.sub.26 H.sub.34 N.sub.2 O.sub.5 S.2HCl    43          ##STR64##      Powder   .sub. 55.95 (55.81)                                         .sub. 6.52 (6.48)                                                .sub. 4.82 (5.01)                                  C.sub.25 H.sub.31 N.sub.2 O.sub.5 SF.2HCl.1/                                  2H.sub.2 O    44          ##STR65##      140-150  .sub. 52.71  (52.44)                                         .sub. 5.82 (5.99)                                                .sub. 4.79 (4.89)                                  C.sub.19 H.sub.27 NO.sub.6 S.HCl    45          ##STR66##      205-210  .sub. 52.57 (52.59)                                         .sub. 6.72 (6.50)                                                .sub. 3.19 (3.23)                                  C.sub.20 H.sub.30 N.sub.2 O.sub.5 S.1/2H.sub                                  .2 O    46          ##STR67##      (Free base 142-145)                                  .sub. 57.45 (57.25)                                         .sub. 7.40 (7.45)                                                .sub. 6.71 (6.68)                                  C.sub.19 H.sub.29 NO.sub.5 S.HCl    47    N(C.sub.2 H.sub.5).sub.2                         185-188  .sub. 54.07                                         .sub. 7.23                                                .sub. 3.34                                  (54.34)                                         (7.20) (3.34)                                  C.sub.20 H.sub.29 NO.sub.5 S.HCl.1/2H.sub.2                                  O    48          ##STR68##      Powder   .sub. 54.51 (54.47)                                         .sub. 7.22 (7.09)                                                .sub. 3.23 (3.18)    __________________________________________________________________________

EXAMPLE 49

Methyl 7-methyl-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate(1.7 g) is alkylated with 3-(4-phenylpiperazin-1-yl)propylchloride inthe same manner as described in Example 1 to give methyl7-methyl-3-oxo-4-]3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate(0.9 g) as a colorless oil.

Mass spectrum (m/e): 454(M⁺)

IR ν_(max) ^(neat) cm⁻¹ : 1760, 1730 (C=0).

NMR (CDCl₃) δ: 2.22 ppm(3H,s,C₇ --CH₃), 3.72 ppm(3H, s,CO₂ CH₃), 4.62ppm(2H, double doublet, C₂ --H).

The hydrochloride [white crystals; mp, 140°-150° C. (decomp.)].

Elemental Analysis for C₂₅ H₃₀ N₂ O₄ S.2HCl.1/2H₂ O Calcd.: C,55.96;H,6.20; N,5.22 Found : C,56.11; H,6.19; N,5.11.

EXAMPLE 50

Methyl 7-chloro-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate isalkylated with 3-(4-phenylpiperazin-1-yl)propylchloride in the samemanner as described in Example 1 to give methyl7-chloro-3-oxo-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylatewhich is isolated as the hydrochloride [(white crystals), mp, 197°-199°C.].

Elemental Analysis for C₂₄ H₂₇ N₂ O₄ SCl.2HCl.1/4H₂ O Calcd.: C,52.18;H,5.38; N,5.07 Found : C,52.11; H,5.11; N,4.98.

EXAMPLE 51

Methyl7-methyl-3-oxo-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate(0.9 g) is reduced by sodium borohydride in the same manner as describedin Example 12 to give methyl cis- andtrans-3-hydroxy-7-methyl-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.

cis-Isomer (colorless oil)

IR ν_(max) ^(neat) cm⁻¹ : 3540(OH), 1740(C=0)

NMR (CDCL₃) δ: 2.35 ppm(3H,s,C₇ --CH₃) 3.75 ppm(3H,s,CO₂ CH₃)

The hydrochloride of cis-isomer (white powder).

Elemental Analysis for C₂₅ H₃₂ N₂ O₄ S.1.5HCl Calcd.: C,58.73; H,6.60;N,5.48 Found : C,58.68; H,6.96; N,5.31.

trans-Isomer (colorless oil)

IR ν_(max) ^(neat) cm⁻¹ : 3550(OH), 1730(C=0)

NMR (CDCl₃ ) δ: 2.25 ppm (3H,s,C₇ --CH₃) 3.52 ppm (3H,s,CO₂ CH₃)

The hydrochloride of trans-isomer (white crystals, mp 145°-155° C.).

Elemental Analysis for C₂₅ H₃₂ N₂ O₄ S.2HCl.1/4H₂ O Calcd.: C,56.23;H,6.51; N,5.25 Found : C,56.39; H,6.53; N,5.24.

EXAMPLE 52

Methyl7-chloro-3-oxo-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateis reduced by sodium borohydride in the same manner as described inExample 12 to give methyl cis- andtrans-7-chloro-3-hydroxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.The hydrochloride of cis-isomer (white crystals, mp 205°-207° C.)

Elemental Analysis for C₂₄ H₂₉ N₂ O₄ SCl.2HCl.1/2H₂ O Calcd.: C,51.57;H,5.77; N,5.01 Found : C,51.77; H,5.79; N,4.97.

The hydrochloride of trans-isomer [white crystals, mp 150°-160° C.(decomp.)].

Elemental Analysis for C₂₄ H₂₉ N₂ O₄ SCl.2HCl Calcd.: C,52.42; H,5.68;N,5.09 Found : C,52.24; H,5.76; N,4.97.

EXAMPLE 53

Methylcis-4-(3-chloropropyl)-3-hydroxy-7-methyl-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate0.3 g is treated with 4-phenylpiperidine in the same manner as describedin Example 39 to give methylcis-3-hydroxy-7-methyl-4-[3-(4-phenylpiperidin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate0.3 g as a colorless oil.

IR ν_(max) ^(neat) cm⁻¹ : 3530(OH), 1740(C=0)

NMR (CDCl₃) δ: 2.22 ppm(3H,s,C₇ --CH₃) 3.72 ppm(3H,s,CO₂ CH₃)

The hydrochloride (white powder).

Elemental Analysis for C₂₆ H₃₃ NO₄ S.HCl.1/2H₂ O Calcd.: C,62.32;H,7.04; N,2.80 Found : C,62.41; H,7.06; N,2.70.

EXAMPLE 54

Methylcis-4-(3-chloropropyl)-3-hydroxy-7-methyl-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateis treated with N-methyl-3,4-dimethoxyphenethylamine in the same manneras described in Example 39 to give methylcis-3-hydroxy-7-methyl-4-{3-[N-methyl-2-(3,4-dimethoxyphenyl)-ethylamino]propyl}-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylatewhich is isolated as the hydrochloride (amorphous powder).

Elemental Analysis for C₂₆ H₃₄ NO₆ S HCl.1/2H₂ O Calcd.: C,58.36;H,6.97; N,2.62 Found : C,58.21; H,7.21; N,2.49.

EXAMPLE 55

A mixture of4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol 500mg, N-phenylpiperazine (500 mg), potassium iodide (50 mg), potassiumcarbonate (400 mg) and N,N-dimethylformamide (10 ml) is heated at 80° C.for 8 hours with stirring. The reaction mixture is poured into water,extracted with ethyl acetate. The organic layer is washed with water,dried over anhydrous sodium sulfate and evaporated to dryness in vacuo.The residue is submited to column chromatography on silica gel elutingwith hexane-ethyl acetate-methanol (10:10:1) to givecis-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol(colorless oil) which is isolated as the dihydrochloride (amorphouspowder).

Elemental Analysis for C₂₃ H₃₀ N₂ O₃ S.2HCl.1/2H₂ O Calcd.: C,55.64;H,6.70; N,5.64 Found : C,55.95; H,6.53; N,5.47.

400 MHz NMR (d₆ -DMSO) δ: 3.206 ppm(1H,multiplet,J=8.1, 3.8, and 4.6Hz,C₄ --H), 3.776 ppm(1H,double doublet, J=12.2 and 8.5 Hz,C₂ --H),4.017 ppm(1H,double doublet, J=12.2 and 3.8 Hz,C₂ --H), 4.152ppm(1H,double triplet, J=8.5,3.8 and 3.8 Hz,C₃ --H).

EXAMPLE 56

To a solution of7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-diethylcarboxamide(1.8 g) in ethanol (15 ml) is added sodium borohydride (0.3 g). Thereaction mixture is stirred at room temperature for 5 hours, then pouredinto ice-water and extracted with ethyl acetate. The organic layer iswashed with saturated aqueous sodium chloride solution, dried overanhydrous sodium sulfate and evaporated to dryness in vacuo. Theobtained residue is submited to column chromatography on silica geleluting with ethyl acetate-hexane (1:1) to give3-hydroxy-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-diethylcarboxamide(1.48 g) as a colorless oil. (IR ν_(max) ^(neat) cm⁻¹ : 3400, 1635).

Thus obtained alcohol 300 mg is reduced by sodium monoacetoxyborohydridein the same manner similar to that described in Example 23 and submitedto column chromatography on silica gel eluting with methylenechloride-methanol (10:1) to givecis-4-diethylaminomethyl-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-olas a colorless oil which is crystallized as the hydrochloride frommethanol-ethyl acetate (pale yellow prisms (138 mg), mp 160°-162° C.).

Elemental Analysis for C₁₅ H₂₃ NO₃ S.HCl Calcd.: C,53.96; H,7.25; N,4.20Found : C,54.11; H,7.44; N,4.13.

400 MHz NMR (d₆ -DMSO) : 3.719 ppm(1H,double doublet, J=12.5 and 8.31Hz,C₂ --H), 3.819 ppm(1H,double triplet, J=7.8,3.9 and 3.9 Hz,C₄ --H),4.121 ppm(1H,double doublet, J=12.5 and 3.9 Hz,C₂ --H), 4.297ppm(1H,double triplet, J=8.3,3.9 and 3.9 Hz,C₃ --H).

EXAMPLE 57

Methylcis-7-chloro-4-(3-chloropropyl)-3-hydroxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate0.15 g is treated with N-methyl-2-(3,4-dimethoxyphenyl)ethylamine in thesame manner as described in Example 39 to give 0.06 g of methylcis-7-chloro-3-hydroxy-4-{3-[N-methyl-2-(3,4-dimethoxyphenyl)ethylamino]propyl}-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate0.06 g as a colorless oil, which is treated with hydrogen chloride togive the hydrochloride as an amorphous powder.

Elemental Analysis for C₂₅ H₃₂ ClNO₆ S.HCl.1/2H₂ O Calcd.: C,54.05;H,6.17; N,2.52 Found : C,54.05; H,6.04; N,2.57.

EXAMPLE 58

Optical resolution of (±) methylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate(±) Methylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate(1.3 g) and S-(+)-1,1'-binaphthyl-2,2'-diyl hydrogenphosphate (1.0 g)are dissolved in methanol (50 ml). The solution is evaporated in vacuo.The residue is dissolved in acetone - methanol and allowed to stand in arefrigerator. The crystalline deposite is filtered off andrecrystallized three times from acetone-methanol to yield white crystals([α]_(D) ²⁵ +175.5 (c=1.01, methanol).

A suspension of the obtained crystals in methylene chloride is treatedwith lN sodium hydroxide solution. The organic layer is washed withwater, dried over anhydrous sodium sulfate and evaporated in vacuo togive a free base as a colorless oil. The obtained base is dissolved inethanol, treated with hydrogen chloride and evaporated in vacuo. Theresidue is tritulated with methanol-ethyl ether to give (-) methylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylatedihydrochloride as an amorphous powder.

[α]_(D) -102.0° (c=0.54 in methanol)

Elemental Analysis for C₂₅ H₃₂ N₂ O₅ S.2HCl.1/2H₂ O Calcd.: C,54.15;H,6.36; N,5.05 Found : C,53.98; H,6.18; N,4.83.

EXAMPLE 59

In the same manner as described in Example 58, the salt of (±) methylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateand R-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen-phosphate is recrystallizedthree times from acetone-methanol to give white crystals ([α]_(D) ²⁵-172° (c=1.03, methanol)]. The obtained salt is treated with lN sodiumhydroxide, followed by treatment with hydrogen chloride to give (+)methylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylatedihydrochloride as an amorphous powder.

[α]_(D) +110.8° (c=0.48 in methanol)

Elemental Analysis for C₂₅ H₃₂ N₂ O₅ S.2HCl.1/2H₂ O Calcd.: C,54.15;H,6.36; N,5.05 Found : C,54.11; H,5.93; N,4.80.

EXAMPLE 60

A mixture ofcis-3-acetoxy-4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-N-benzylcarboxamide(0.3 g), N-phenylpiperazine (0.13 g), potassium iodide (0.1 g),potassium carbonate (0.12 g) and N,N-dimethylformamide (4 ml) is stirredat 70° C. for 2 hours. The reaction mixture is poured into ice-water (20ml) and extracted with ethyl acetate. The organic layer is washed withwater, dried over anhydrous Na₂ SO₄ and evaporated to dryness in vacuo.The residue is triturated with AcOEt-hexane to givecis-3-acetoxy-7-methoxy-4-[3-(4-phenylpiperazine-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-N-benzylcarboxamide(97 mg) which is isolated as white crystals, mp 178°-180° C. (fromAcOEt)

Mass Spectrum m/e: 589 (M⁺)

Elemental Analysis for C₃₃ H₃₉ N₃ O₅ S.1/4H₂ O Calcd.: C,66.70; H,6.70;N,7.07 Found : C,66.75; H,6.63; N,6.87.

EXAMPLE 61

Methylcis-4-(3-chloropropyl)-3-hydroxy-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateis treated with 4-(2-pyrimidyl)piperazine in the same manner asdescribed in Example 39 to give methylcis-3-hydroxy-7-methoxy-4-[3-[4-(2-pyrimidyl)piperazin-1-yl]propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylatedihydrochloride as an amorphous powder.

Elemental Analysis for C₂₃ H₃₀ N₄ O₅ S.2HCl.3/2H₂ O Calcd.: C, 48.08; H,6.14; N, 9.75 Found : C, 47.93; H, 6.25; N, 9.56.

EXAMPLE 62

Methylcis-3-hydroxy-4-(3-chloropropyl)-8-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateis treated in the same manner as described in Example 39 to give methylcis-3-hydroxy-8-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl-]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylatehydrochloride as colorless crystals.

Melting point: 195°-198° C. (recrystallized from ethanol)

Elemental Analysis for C₂₅ H₃₂ N₂ O₅ S.HCl.1/4H₂ O Calcd.: C, 58.47; H,6.57; N, 5.46 Found : C, 58.43; H, 6.44; N, 5.62.

EXAMPLE 63

Methyltrans-3-hydroxy-8-methoxy-4-(3-chloropropyl)-3,4-dihydro-2H,-1,5-benzoxathiepin-4-carboxylateis treated in the same manner as described in Example 39 to give methyltrans-3-hydroxy-8-methoxy-4-[3-(4-phenylpiperazin-1-yl)-propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylatedihydrochloride as colorless crystals.

Melting point: 160°-175° C. (decomp.) (recrystallized from ethanol-ethylether)

Elemental Analysis for C₂₅ H₃₂ N₂ O₅ S.2HCl.1/2H₂ O Calcd.: C, 54.12; H,6.36; N, 5.05 Found : C, 54.08; H, 6.02; N, 5.03.

EXAMPLE 64

A mixture of methylcis-7-benzyloxy-3-hydroxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylatedihydrochloride (0.8 g), methanol (100 ml), concentrated hydrochloricacid (0.3 ml) and 10% palladium carbon (1.8 g) is hydrogenated underhydrogen stream at room temperature for 48 hours. After filtration, thefiltrate is evaporated to dryness in vacuo.

The residue is mixed with ethyl acetate and 5% sodium bicarbonatesolution. The organic layer is separated, washed with water, dried overanhydrous sodium sulfate and evaporated to dryness in vacuo. The residueis submitted to silica gel column chromatography elutingwith-n-hexaneethyl acetate (2:3) to give methylcis-3,7-dihydroxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateas white crystals.

Melting point: 195°-197° C. (recrystallized from ethyl acetate)

Elemental Analysis for C₂₄ H₃₀ H₂ O₅ S Calcd.: C, 62.86; H, 6.59; N,6.11 Found : C, 62.61; H; 6.50; N, 5.88.

EXAMPLE 65

A mixture of methylcis-4-(3-chloropropyl)-3-hydroxy-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate(2.0 g), lN NaOH (8 ml) and methanol (20 ml) is stirred at roomtemperature for 14 hours. The reaction mixture is poured into water andwashed with ethyl acetate. The aqueous layer is acidified with 6N HCland extracted with ethyl acetate. The organic layer is washed withwater, dried over anhdrous sodium sulfate and evaporated to dryness invacuo. The residue is recrystallized from ethyl acetate to givecis-4-(3-chloropropyl)-3-hydroxy-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylicacid as colorless prisms (mp: 174°-176° C.). The obtained acid (0.7 g)is heated at 180° C. for 30 minutes to givetrans-4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-olas a colourless oil.

A mixture oftrans-4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol(0.1g) and N-phenylpiperazine (0.2 g) is stirred at 90° C. for 2 hours. Thereaction mixture is purified by silica gel column chromatography elutingwith n-hexane-ethyl acetate methanol (10:10:1) and treated, withethanolic hydrogen chloride to givetrans-7-methoxy-4-[3-(4-phenylpiperazine-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-3-oldihydrochloride as an amorphous powder.

Elemental Analysis for C₂₃ H₃₀ N₂ O₃ S.2HCl Calcd.: C, 56.67; H, 6.62;N, 5.44 Found : C, 56.42; H, 6.85; N, 5.51.

EXAMPLE 66

A mixture of 1.0 g of methylcis-4-(3-chloropropyl)-3-hydroxy-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate,0.67 g of N-4-hydroxyphenylpiperazine and 2 ml of N,N-dimethylacetamideis stirred at 90° C. for 3 hours. Water is added to the mixture and themixture is extracted with ethyl acetate. The organic layer are combined,washed with water and dried and the solvent is evaporated off underreduced pressure. The residue is purified by silica gel columnchromatography [eluent: hexane-ethyl acetate-methanol (20:20:1)]to give0.7 g of methylcis-3-hydroxy-4-[3-[4-(4-hydroxyphenyl)piperazin-1-yl]propyl]-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateas a pale yellow oil. This product is converted to a white powder of thedihydrochloride.

Melting point: 240°-245° C. (decomp.)

Elemental Analysis for C₂₅ H₃₂ N₂ O₆ S.2HCl Calcd.: C, 53.47; H, 6.10;N, 4.99 Found : C, 53.20; H, 5.97; N, 5.21.

EXAMPLE 67

A mixture of 1.0 g methylcis-4-(3-chloropropyl)-3-hydroxy-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate,1.2 g of N-2-hydroxyphenylpiperazine, 0.97 g of potassium carbonate and6 ml of N,N-dimethylacetamide is stirred at 85° C. for 5 hours. Water isadded to the mixture and the mixture is extracted with ethyl acetate.The organic layers are combined, washed with water and dried and thesolvent is evaporated off under reduced pressure. The residue ispurified by silica gel column chromatography [eluent: hexane-ethylacetate-methanol (20:20:1)]to give 0.7 g of methylcis-3-hydroxy-4-[3-[4-(2-hydroxyphenyl)-piperazin-1-yl]propyl]-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateas a pale yellow oil. This product is converted to a white powder of thedihydrochloride.

Melting point: 175°-190° C. (decomp.)

Elemental Analysis for C₂₅ H₃₂ H₂ O₆ S.2HCl.1/2H₂ O Calcd.: C, 52.63; H,6.18; N, 4.91 Found : C, 52.91; H, 5.94; N, 4.95.

EXAMPLE 68

To 600 ml of methanol is dissolved 1.16 g of methylcis-7-benzyloxy-3-hydroxy-4-[3-[4-(4-hydroxyphenyl)piperazin-1-yl]propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate,and 1.0 g of 10% palladium carbon and 0.1 ml of concentratedhydrochloric acid are added to the mixture, followed by stirring underhydrogen atmosphere at ambient temperature and under atmosphericpressure. The catalyst is filtered off and the solvent is evaporatedoff. The residue is purified by silica gel column chromatography[eluent: hexane- ethyl acetate-methanol (12:12:1)]. The obtained crudeproduct is recrystallized from ethyl acetate to give 0.62 g of methylcis-3,7-dihydroxy-4-[3-[4-(4-hydroxyphenyl)piperazin-1-yl]propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylateas a white powder. Melting point: 226°-229° C.

Elemental Analysis for C₂₄ H₃₀ N₂ O₆ S Calcd.: C, 60.74; H, 6.37; N,5.90 Found : C, 60.47; H, 6.39; N, 5.71.

Melting points in Reference Examples and Examples shows the values asmeasured by a micro melting point apparatus (Yanagimoto, Japan) unlessotherwise specified.

EXPERIMENT EXAMPLE 1

Serotonin S₂ -receptor blocking activity (in vitro) of the compound ofthe present invention:

[Experimental method]

The experiment was carried out in acccordance with the method of Bevan &Osher (Agents Actions, 2, 257, 1972) with a few modifications. The heartremoved from a hog immediately after being slaughtered at aslaughterhouse was preserved under ice-cooling, and the left circumflexcoronary artery was dissected within 3 hours. The coronary artery wascut into a ring preparation of about 3 mm in width, which was suspendedin a double-wall organ bath containing 20 ml of the Krebs-Henseleitsolution using a pair of suspending hooks. One of the suspending hookswas fixed to the bottom of the organ bath, While the other was connectedto a strain-gaige transducer, and the constriction of the ringpreparation of the porcine coronary artery was isometrically measuredand recorded on a polygraph recorder. The organ bath was maintained at37° C., and the Krebs-Henseleit solution was saturated with a mixed gasof 97% O₂ +3% CO₂, with the Krebs-Henseleit solution being composed of118.3 mM NaCl, 4.7 mM KCl, 1.2 mM KH₂ PO₄ , 2.58 mM CaCl₂ ·2H₂ O, 1.15mM MgSO₄ ·7H₂ O, 25 mM NaHCO₃ and 11.1 mM glucose.

In 1 to 2 hours when the blood vessel preparation showed stable restingtension, the resting tension was readjusted to be 2 g, and 10⁻⁶ Mserotonin (final concentration) was added to the organ bath at theinterval of about 1 hour to check the responsiveness of the preparation.When the reaction of the blood vessel to 2 to 3 additions of serotoninbecame stable, a concentration of the test compound was added to theorgan bath 10 minutes prior to subsequent addition of serotonin. Theserotonergic blocking effect of the test compound was calculated fromthe magnitudes of constriction caused by serotonin before and after theaddition of the test compound.

[Experimental results]

The results of the experiment with regard to the compounds of thepresent invention are shown in Table 8.

                  TABLE 8    ______________________________________    Serotonin S.sub.2 -receptor blocking effect in porcine coronary    artery preparation.                         No. of  Inhibition of constric-    Example number               Concn. (M)                         cases   tion by serotonin, %    ______________________________________     1         10.sup.-5 3       85.7 ± 9.7               10.sup.-6 3       67.2 ± 8.0    12-(cis-isomer.hy-               10.sup.-6 3       100    drochloride)               10.sup.-7 4       76.0 ± 5.3    28         10.sup.-5 3       93.3 ± 6.9               10.sup.-6 3        73.5 ± 10.2    34         10.sup.-5 2       100               10.sup.-6 3       83.3 ± 1.0    41         10.sup.-5 2       82.8               10.sup.-6 3       27.2 ± 1.5    40         10.sup.-6 3       87.8 ± 3.0               10.sup.-7 3       24.7 ± 2.2    44         10.sup.-6 3       99.2 ± 0.8               10.sup.-7 3        12.2 ± 37.0    33         10.sup.-6 2       77.3    (cis-isomer)               10.sup.-7 2        2.6    26         10.sup.-5 2       99.8               10.sup.-6 2       35    42         10.sup.-6 3       87.5  9.0               10.sup.-7 3       50.4  7.0    ______________________________________

EXPERIMENTAL EXAMPLE 2

In the same manner as descirbied in Experiment Example 1, theserotonergic blocking effect of the test compound was measured. Theresults are shown in Table 9.

                  TABLE 9    ______________________________________                          No. of  Inhibition of constric-    Example number                Concn. (M)                          cases   tion by serotonin (%)    ______________________________________    39          10.sup.-7 3       57 ± 7.1    (monohydro-    chloride)    59          10.sup.-7 3       70.7 ± 2.0    ______________________________________

EXPERIMENT EXAMPLE 3

Oral serotonergic blocking activity of the compounds of the presentinvention.

[Experimental method]

The experiment was carried out using beagle dogs of male weighing from10 to 14 kg. Polyethylene tubes were previously implanted into thefemoral artery and vein for measurement of systemic blood pressure andfor intravenous administration of a test compound, respectively. Thesurgical operation for implantation of the polyethylene tubes wasperformed under strile conditions under anesthesia with sodiumpentobarbital (30 mg/kg intravenously administered). The other ends ofthe polyethylene tubes were led to the dorsal part subcutaneously andexteriorized.

Two to 3 days after the operation, the experiment was carried out. Thepolyethylene tube kept inserted into the artery was connected to apressure transducer, and the systemic blood pressure was measured andrecorded continuously on a polygraph recorder. When 3 to 30 μg/kg ofserotonin was administered intravenously through the polyethylene tubekept inserted into the femoral vein, a transient hypertensive reactionwas observed in a dose-dependent manner, and when 30 μg/kg of serotoninwas, for example, given repeatedly at the interval of about 30 minutes,a reproducible hypertensive reaction was noted. Therefore, 30 μg/kg ofserotonin was used in order to investigate into the effect through oraladministration of the compound of the present invention. After it wasconfirmed that 2 to 3 intravenous administrations of 30 μg/kg ofserotonin at the interval of about 30 minutes gave rise to a stablehypertensive reaction, the compound (I) of the present invention[Example 12 (cis isomer.dihydrochloride)]was administered orally indoses of 0.1, 0.3 and 1.0 mg/kg, and the hypertensive reaction to 30μg/kg of serotonin was repeatedly examined, thereafter, until thepre-drug level of the hypertension reaction was attained. [Experimentresults]

The results of the experiment are shown in Table 10. The compound ofExample 12 (cis isomer.dihydrochloride), when given in doses of not lessthan 0.1 mg/kg, exhibited dose-dependent and persisting inhibitionagainst the hypertensive reaction to serotonin.

                  TABLE 10    ______________________________________    Inhibition of the hypertensive reaction to serotonin (30    μg/kg, i.v.) in unanesthetized beagle dogs.                             The time when the                   Maximum   maximum inhibition    Dose  No. of   inhibition                             developed    Duration    mg/kg cases    % hr. after administration                                        hr.    ______________________________________    0.1   4        27.8      2            4    0.3   4        40.9      3            6    1.0   3        72.0      3            8    ______________________________________

EXPERIMENT EXAMPLE 4 Calcium-antagonistic action

[Experimental method]

The mesenterium was excised from a spontaneously hypertensive rat (14weeks of age, male), and perfused through the mesenteric artery with theKrebs-Henseleit solution under warming at 37° C. The basal flow rate waskept in about 4 ml/min for the perfusion pressure to be about 40 mmHg.Employed as an indication of calcium antagonism was inhibition of theincrease in the perfusion pressure provoked by 10 mg/preparation of KClinjected into the mesenteric artery. The test compound was injected intothe artery 30 minutes prior to the injection of KCl.

[Experimental results]

The results are shown in Table 11. In the cases of non-treatmented,control group, the increase in the perfusion pressure due to KCl was 73±20 (mean value for 8 cases ±S.E.M.) mmHg, which was designated as 100%in the table. The compound of Example 12 (cis), when given in doses of10⁻⁷ to 3×10⁻⁶ M, exhibited dose-dependent and significant inhibition ofthe KCl-induced increase in the perfusion pressure.

                  TABLE 11    ______________________________________    Calcium antagonistic action in isolated, perfused    mesenterial preparations of rats.                        Change in perfusion pressure upon    Group     Dose (M)  injection of KCl (%) (No. of cases)    ______________________________________    Control   --        100 (8)    Example 12(cis)              10.sup.-7 84 ± 3* (3)              10.sup.-6 51 ± 14* (5)              3 × 10.sup.-6                        30 ± 2* (3)    ______________________________________

EXPERIMENT EXAMPLE 5 Diuretic action

[Experimental method]

Four groups of 5 spontaneously hypertensive rats (13 week of age, male)each were used in the experiment. The test compound was suspended inisotonic salire with a small amount of gum arabic and administeredorally in the volume of 25 ml/kg. Isotonic saline containing gum arabicalone was given to the control group. After the administration, each ratwas placed in a metabolism cage for collection of urine for 5 hours. Thevolume of urine and the amounts of urinary Na⁺ and K⁺ excreted weremeasured. The concentrations of Na⁺ and K⁺ were determined using a flamespectrophotometer (Hitachi type 205 DT).

[Experimental results]

The results are shown in Table 12. The compound of Example 12 (cisisomer.dihydrochloride), when administered orally in a dose of 3 mg/kg,tended to promote the secretion of urine as well as of Na⁺ and K⁺, andwhen given orally in a dose of 10 mg/kg, brought about a significantincrease in the urinary volume, and tendency toward increases in Na⁺ andK⁺ excretion. Thirty mg/kg gave rise to significant increases in theurinary volume and in Na⁺ and K⁺ excretion.

                  TABLE 12    ______________________________________    Diuretic action in spontaneously hypertensive rats.           Dose            Volume of           mg/kg   No. of  urine ml/100                                    Na.sup.+                                            K.sup.+    Group  orally  animals g/5 hr   μeq/100                                            g/5 hr    ______________________________________    Control           --      5       1.02 ± 0.10                                    128 ± 15                                            59 ± 8    Example            3      5       1.41 ± 0.18                                    160 ± 19                                            77 ± 5    12(cis)           10      5       1.74 ± 0.15*                                    169 ± 20                                            81 ± 8           30      5       1.97 ± 0.20**                                    192 ± 15*                                            88 ± 9*    ______________________________________     Student's ttest      *P < 0.05,      **P< 0.01

EXPERIMENT EXAMPLE 6

In vivo antithrombotic action in the coronary circulation ofanesthetized dogs.

[Experimental method]

Adult mongrel dogs, which underwent thoracotomy under anesthesia withsodium pentobarbital, were used. Intracoronary thrombosis was producedin accordance with the method of Folts et al. [Circulation, 54, 365(1976)]. In brief, an arterial cannula was inserted into the leftcircumflex coronary artery, and the arterial blood was led from thecommon carotid artery through an extracorporeal circuit to perfuse thearterial area. The coronary blood flow was measured with anelectromagnetic blood flow probe placed in the extracorporeal circuit. Aplastic constrictor was set around the circumflex coronary artery tonarrow it by about 70 to 80%. The formation of intra-coronary thrombiwas judged by the periodically found decrease and increase in coronaryblood flow, because it was demonstrated that platelet thrombi are formedat the narrowed region due to turbulant blood flow, and washed away byincreased pressure gradient. And the frequent formation and removal ofthe thrombi results in periodical change of the coronary blood flow.Thus, the in vivo antithrombotic activity was assessed in terms of theeffect of the test compound on the frequency of the change in thecoronary blood flow.

The test compound was administered intravenously.

[Experimental results]

When the constrictor was set around the circumflex coronary artery, thecoronary blood flow decreased gradually from the initial rate of 20-30ml/min to several ml/min, and increased abruptly. The decrease andincrease in the coronary blood flow were found to take placeperiodically, and the frequency was 5 to 15/30 minutes.

The compound of Example 12 (cis isomer.dihydrochloride), whenadministered intravenously in doses of 1 μg/kg and more, wasdemonstrated to diminish the frequency of the periodical changes in thecoronary blood flow in a dosedependent manner (Table 13), indicatingthat the compound of Example 12 (cis isomer.dihydrochloride) inhibitedthe formation of intra-coronary thrombi caused by blood flowdisturbances in vivo.

                  TABLE 13    ______________________________________    Effect on the frequency of periodical changes in the    coronary blood flow.                         0 to 30 min.                                     30 to 60 min.            Before adminis-                         after adminis-                                     after adminis-    Dose    tration      tration     tration    ______________________________________     1 μg/kg            8.86 ± 1.94                         5.71 ± 1.06                                     3.8 ± 2.62     3      7.25 ± 1.03                         4.75 ± 1.80                                     0***    10       8.0 ± 1.73                          0.33 ± 0.33*                                     0***    ______________________________________

The values denote the frequency of periodical changes in the coronaryblood flow over the 30-minute period in terms of mean value ± standarderror. *: P<0.05, ***: P<0.001

EXPERIMENTAL EXAMPLE 7 An action to relieve cerebral vasospasm afterexperimental subarachnoideal hemorrhage

[Experimental method]

Six beagle dogs weighing 10 to 14 kg were used. For cerebrovascularangiography, a polyethylene cannula was previously implanted chronicallyinto the right vertebral artery under pentobarbital anesthesia (30mg/kg, intravenous administration). Under pentobarbital anesthesia,cerebrovascular angiography was done twice every 2 seconds immediatelyafter injection of 10 ml of a contrast media, iodamide glutamineinjection, through the chronically implanted cannula by use of aroentogenograph (MEDIX-50U). Subarachnoideal hemorrhage was induced byinjection of 5 ml of fresh autologous blood taken from a vein of thelower extremity into the cisterna magna with a spinal needle underpentobarbital anesthesia 2 days after implantation of the cannula.Cerebrovascular angiography was done before, and 3, 6 and 13 days aftersubarachnoideal hemorrhage, and the diameter of the basilar artery wasmeasured on the X-ray photograph.

The animals were divided into 2 groups of 3 head each, and the one groupwas taken as the control, and the other group was given the compound ofExample 39 (monohydrochloride salt). The compound concerned was given atdcses of 30 mg/kg orally at the day of subarachnoideal hemorrhage, of 1mg/kg intravenously immediately after subarachnoideal hemorrhage, and of30 mg/kg orally consecutively every day until the 13th day aftersubarachnoideal hemorrhage.

[Experimental results]

The diameter of the basilar artery before subarachnoideal hemorrhage andchange in the diameter after subarachnoideal hemorrhage are shown inTable 14. In the control group, the basilar arterial diamter decreasedby about 40 and 60% 3 and 6 days after subarachnoideal hemorrhage,respectively, indicating occurrence of cerebral vasospasm. On the otherhand, in the group treated with the compound, the decrease in thebasilar arterial diamter was slight, and the degree of the decrease wassignificantly lower as compared with that in the control group.

                                      TABLE 14    __________________________________________________________________________                     Change in arterial diameter    Arterial diameter                     after subarachnoideal    before subarachnoi-                     hemorrhage (%)    Group         deal hemorrhage (mm)                     3 days after                              6 days after                                      13 days after    __________________________________________________________________________    Control         1.47 ± 0.02                     -38.3 ± 3.7                              -59.3 ± 3.8                                      -12.7 ± 9.9    group    Treated          1.07 ± 0.07*                       -2.7 ± 2.7**                              -20.7 ± 12.0*                                      -5 ± 5    group    __________________________________________________________________________     *P < 0.05     **P < 0.01     (Student ttest)

EXPERIMENT EXAMPLE 8 An action to improve renal circulation

[Experimental method]

Beagle dogs (normal blood pressure) weighing 9 to 14 kg were used.Laparotomy was done along the abdominal middle line under pentobarbitalanesthesia. In order to measure renal blood flow, the left renal arterywas dissected free, and an electromagnetic flow probe was set around theartery. A polyethylene tubing was retrogradely inserted and fixed intothe abdominal aorta to measure systemic blood pressure. The other endsof the lead wire of the electromagnetic flow probe and of thepolyethylene tubing were passed beneath the skin and exteriorized at theback of the neck.

One week or more after the surgical operation, the animals weresubjected to theexperiment under unanesthetized condition. Renal bloodflow was measured by an electromagnetic flowmeter, and systemic bloodpressure by a pressure transducer. Heart rate was measured with apulse-rate tachometer triggered by blood pressure pulse waves.

The test compound [Example 39 (monohydrochloride salt)]was orallyadministered, and an interval of 3 days or more was allowed to elapsebetween administrations, when the compound was administered repeatedlyin the same individual.

[Experimental results]

In this series of experiment, when lactose (10 mg/kg, the number ofexperiments: 7) was orally administered as a control, no change insystemic blood pressure, heart rate and renal blood flow was noted over7 hours of observation period. By administration of 3 or 10 mg/kg of thetest compound, systemic blood pressure was slightly lowered in adose-dependent manner, while heart rate was not affected. Renal bloodflow, however, was markedly increased by these doses, the maximumincreases being by about 23 and 46%, respectively, and the action lastedover 7 hours of observation. The results are shown in Table 15.

                  TABLE 15    ______________________________________           No. of   Maximum changes 2 to 3 hours after    Dose   experi-  administration (%)    (mg/kg,           mental   Systemic blood      Renal blood    orally)           cases    pressure    Heart rate                                        pressure    ______________________________________     3     3        - 6.6 ± 4.0                                +2.8 ± 3.7                                        +23.2 ± 9.4    10     3        -11.3 ± 0.9                                +3.8 ± 5.9                                        +46.1 ± 8.0    ______________________________________

EXPERIMENT EXAMPLE 9

In the same manner as described in Experiment Example 1, theserotonergic blocking effect of the test compound was measured. Theresults are shown in Table 16.

                  TABLE 16    ______________________________________                            Inhibition of constric-    Example number                  Concn. (M)                            tion by serotonin (%)    ______________________________________    61            10.sup.-5 68    62            10.sup.-5 92                  10.sup.-6 71    63            10.sup.-5 96    64            10.sup.-5 79    65            10.sup.-5 72    66            10.sup.-5 100                  10.sup.-6 100                  10.sup.-7 62    67            10.sup.-5 100    68            10.sup.-5 100    ______________________________________

PREPARATION EXAMPLE

The compounds (I) of the present invention can be used, for example, asa treatment agent for ischemic cardiopathies, in the following examplesof formulation.

    ______________________________________    1. Tablets    ______________________________________    (1) Methyl cis-3-hydroxy-7-methoxy-4-[3-(4-phenyl-                                    10     g        piperazin-1-yl)propyl] -3,4-dihydro-2H--1,5-        benzoxathiepin-4-carboxylate.hydrochloride    (2) Lactose                     90     g    (3) Corn starch                 29     g    (4) Magnesium stearate          1      g        For 1000 tablets,           130    g    ______________________________________

The above ingredients (1) and (2) and 17 g of (3) are blended, andgranulated together with a paste prepared from 7 g of the ingredient(3). 5 of the ingredient (3) and the ingredient (4) are added to theresulting granules, and the mixture is compressed by a tablettingmachine to prepare 1000 tablets of diameter of 7 mm each containing 10mg of the ingredient (1).

    ______________________________________    2. Capsules    ______________________________________    (1) Methyl cis-3-hydroxy-7-methoxy-4-[3-(4-phenyl-                                    10     g        piperazin-1-yl)propyl] -3,4-dihydro-2H--1,5-        benzoxathiepin-4-carboxylate.hydrochloride    (2) Lactose                     135    g    (3) Finely powdered cellulose   70     g    (4) Magnesium stearate          5      g        For 1000 capsules,          220    g    ______________________________________

All of the above ingredients are blended and filled into 1000 capsulesof Gelatin Capsule No. 3 (X Japanese Pharmacopoeia) to prepare 1000capsules each containing 10 mg of the ingredient (1).

    ______________________________________    3. Injectable solution.    ______________________________________    (1) Methyl cis-3-hydroxy-7-methoxy-4-[3-(4-phenyl-                                    10     g        piperazin-1-yl)propyl] -3,4-dihydro-2H--1,5-        benzoxathiepin-4-carboxylate.tartarate    (2) Sodium chloride             9      g    (3) Chlorobutanol               5      g    ______________________________________

All of the ingredients are dissolved in 1000 ml of distilled water, andcharged into 1000 brown ampoules each containing 1 ml of the solution.The air in the ampoules is replaced with nitrogen gas and the ampoulesare sealed. The entire preparation steps are conducted under strileconditions.

What is claimed is:
 1. A compound of the formula: ##STR69## wherein R₁and R₂ are independently hydrogen, halogen, hydroxy, C₁₋₄ alkyl or C₁₋₄alkoxy,R₃ and R₄ are independently hydrogen, (i) C₁₋₄ alkyl which may besubstituted by C₃₋₈ cycloalkyl, halogen, hydroxy, C₁₋₄ alkoxy, C₁₋₅alkanoyloxy, mono- or di-C₁₋₄ alkylamino, C₃₋₈ cycloalkylamino, C₁₋₅alkanoylamino, benzamido, C₁₋₄ alkylthio, carbamoyl, N-C₁₋₄alkylcarbamoyl or N,N-di-C₁₋₄ alkylcarbamoyl, (ii) C₃₋₈ cycloalkyl whichmay be substituted by C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₅ alkanoylamino orhydroxy, (iii) phenyl-C₁₋₄ alkyl which may be substituted by 1 to 3members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino,nitro or hydroxy, or (iv) R₃ and R₄, taken together with the nitrogenatom, form 5 to 7 membered ring which may be substituted by (1) C₁₋₄alkyl, (2) phenyl unsubstituted or substituted by 1 to 3 members ofhalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro orhydroxy, (3) phenyl-C₁₋₄ alkyl unsubstituted or substituted by 1 to 3members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino,nitro or hydroxy, (4) diphenyl-C₁₋₄ alkyl unsubstituted or substitutedby 1 to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy,amino, nitro or hydroxy, (5) triphenyl-C₁₋₄ alkyl unsubstituted orsubstituted by 1 to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,methylenedioxy, amino, nitro or hydroxy, (6) C₁₋₄ alkanoyl, (7) benzoylunsubstituted or substituted by 1 to 3 members of halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxy, (8) phenyl-C₁₋₄alkanoyl unsubstituted or substituted by 1 to 3 members of halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxy, (9)phenyl-C₁₋₄ alkenoyl unsubstituted or substituted by 1 to 3 members ofhalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro orhydroxy or (10) 5 to 7 membered heterocyclic having 1 to 3 nitrogenatoms, X is (1) hydrogen, (2) C₁₋₄ alkyl, (3) C₁₋₄ alkanoyl, (4)hydroxymethyl, (5) C₁₋₅ alkanoyloxymethyl, (6) phenyl-C₁₋₄ alkyl whichmay be substituted by 1 to, 3 members of halogen, C₁₋₄ alkyl, C₁₋₄alkoxy, methylenedioxy, amino, nitro or hydroxy, (7) phenyl which may besubstituted by 1 to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,methylenedioxy, amino, nitro or hydroxy, (8) C₁₋₄ alkoxycarbonyl, (9)phenyl-C₁₋₄ alkoxycarbonyl, (10) carbamoyl which may be substituted by 1to 2 members of C₁₋₄ alkyl, phenyl or phenyl-C₁₋₄ alkyl or (11) carboxy,Y is ##STR70## in which R5 is (i) hydrogen, (ii) C₁₋₆ alkanoyl, (iii)phenyl-C₁₋₆ alkanoyl unsubstituted or substituted by 1 to 3 members ofhalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro orhydroxy, (iv) carbamoyl unsubstituted or substituted by (1) C₁₋₄ alkyl,(2) phenyl unsubstituted or substituted by 1 to 3 members of halogen,C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxy or (3)phenyl-C₁₋₄ alkyl unsubstituted or substituted by 1 to 3 members ofhalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro orhydroxy, m is an integer of 0 to 2 and n is an integer of 1 to 6, or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein R₁ and R₂ are independently hydrogen, halogen, C₁₋₄alkyl or C₁₋₄ alkoxy.
 3. A compound according to claim 1, wherein R₁ andR₂ are independently hydrogen or C₁₋₄ alkoxy.
 4. A compound according toclaim 1, wherein R₃ and R₄ are independently hydrogen, C₁₋₄ alkyl, C₃₋₈cycloalkyl, phenyl-C₁₋₄ alkyl which may be substituted by 1 to 3 membersof halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro orhydroxy or R₃ and R₄, taken together with the nitrogen atom, formmorpholinyl, piperazinyl or piperidyl which may be substituted by (1)C₁₋₄ alkyl, (2) phenyl unsubstituted or substituted by 1 to 3 members ofhalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro orhydroxy, (3) phenyl-C₁₋₄ alkyl unsubstituted or substituted by 1 to 3members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino,nitro or hydroxy, (4) diphenyl-C₁₋₄ alkyl unsubstituted or substitutedby 1 to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy,amino, nitro or hydroxy, (5) triphenyl-C₁₋₄ alkyl unsubstituted orsubstituted by 1 to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,methylenedioxy, amino, nitro or hydroxy, (6) C₁₋₄ alkanoyl, (7) benzoylunsubstituted or substituted by 1 to 3 members of halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxy, (8) phenyl-C₁₋₄alkanoyl unsubstituted or substituted by 1 to 3 members of halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxy, (9)phenyl-C₁₋₄ alkenoyl unsubstituted or substituted by 1 to 3 members ofhalogen C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxyor (10) 5 to 7 membered heterocyclic having 1 to 3 nitrogen atoms.
 5. Acompound according to claim 1, wherein R₃ and R₄, taken together withthe nitrogen atom, form 4-phenylpiperazinyl in which the phenyl group isunsubstituted or substituted by 1 to 3 members of halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxy.
 6. A compoundaccording to claim 1, wherein R₃ and R₄, taken together with thenitrogen atom, form 4-phenylpiperazinyl.
 7. A compound according toclaim 1, wherein X is hydrogen, carboxy, C₁₋₄ alkoxycarbonyl,hydroxymethyl or C₁₋₅ alkanoyloxymethyl.
 8. A compound according toclaim 1, wherein X is C₁₋₄ alkoxycarbonyl.
 9. A compound according toclaim 1, wherein Y is ##STR71## in which R₅ is (i) hydrogen, (ii) C₁₋₆alkanoyl or (iii) carbamoyl unsubstituted or substituted by (1) C₁₋₄alkyl, (2) phenyl unsubstituted or substituted by 1 to 3 members ofhalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro orhydroxy or (3) phenyl-C₁₋₄ alkyl unsubstituted or substituted by 1 to 3members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino,nitro or hydroxy.
 10. A compound according to claim 1, wherein Y ishydroxymethylene.
 11. A compound according to claim 1, wherein m is 0.12. A compound according to claim 1, wherein n is an integer of 2 to 6.13. A compound according to claim 1, wherein n is
 3. 14. A compoundaccording to claim 1, wherein R₁ is hydrogen and R₂ is C₁₋₄ alkoxy. 15.A compound according to claim 1, wherein R₁ is hydrogen and R₂ is C₁₋₄alkoxy which is attached at the 7th position of the benzoxathiepinmoiety.
 16. A compound of the formula: ##STR72## wherein R₆ is phenylwhich may be substituted by 1 to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄alkoxy, methylenedioxy, amino, nitro or hydroxy,R₂, is C₁₋₄ alkoxy, andX is C₁₋₄ alkoxycarbonylor a pharmaceutically acceptable salt thereof.17. A compound according to claim 16, wherein R₆ is phenyl.
 18. Acompound according to claim 16, wherein R₂, is methoxy.
 19. A compoundaccording to claim 16, wherein X is methoxycarbonyl.
 20. The compoundaccording to claim 1, which is methyl7-methoxy-3-oxo-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.
 21. The compound according toclaim 1, which is methylcis-3-acetoxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl-]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.22. The compound according to claim 1, which is ethylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl-]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.23. The compound according to claim 1, which is methylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperidino)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.
 24. The compoundaccording to claim 1, which is methylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)-propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.25. The compound according to claim 1, which is methylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)-propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylatedihydrochloride.
 26. The compound according to claim 1, which is methylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)-propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylatemonohydrochloride.
 27. The compound according to claim 1, which ismethylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)-propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylatemonohydrochloride dihydrate.
 28. The compound according to claim 1,which is (+)methylcis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)-propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.29. A pharmaceutical composition suitable for treatment of ischemiccardiopathy, thrombosis, hypertension or cerebral circulatory disorderwhich comprises, as an active ingredient, an effective amount of acompound of the formula: ##STR73## wherein R₁ and R₂ are independentlyhydrogen, halogen, hydroxy, C₁₋₄ alkyl or C₁₋₄ alkoxy,R₃ and R₄ areindependently hydrogen, (i) C₁₋₄ alkyl which may be substituted by C₃₋₈cycloalkyl, halogen, hydroxy, C₁₋₄ alkoxy, C₁₋₅ alkanoyloxy, mono- ordi-C₁₋₄ alkylamino, C₃₋₈ cycloalkylamino, C₁₋₅ alkanoylamino, benzamido,C₁₋₄ alkylthio, carbamoyl, N-C₁₋₄ alkylcarbamoyl or N,N-di-C₁₋₄alkylcarbamoyl, (ii) C₃₋₈ cycloalkyl which may be substituted by C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₅ alkanoylamino or hydroxy, (iii) phenyl-C₁₋₄alkyl which may be substituted by 1 to 3 members of halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxy, or (iv) R₃ and R₄,taken together with the nitrogen atom, form 5 to 7 membered ring whichmay be substituted by (1) C₁₋₄ alkyl, (2) phenyl unsubstituted orsubstituted by 1 to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,methylenedioxy, amino, nitro or hydroxy, (3) phenyl-C₁₋₄ alkylunsubstituted or substituted by 1 to 3 members of halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxy, (4) diphenyl-C₁₋₄alkyl unsubstituted or substituted by 1 to 3 members of halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxy, (5)tripheryl-C₄ alkyl unsubstituted or substituted by 1 to 3 members ofhalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro orhydroxy, (6) C₁₋₄ alkanoyl, (7) benzoyl unsubstituted or substitututedby 1 to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy,amino, nitro or hydroxy, (8) phenyl-C₁₋₄ alkanoyl unsubstituted orsubstituted by 1 to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,methylenedioxy, amino, nitro or hydroxy, (9) phenyl-C₁₋₄ alkenoylunsubstituted or substituted by 1 to 3 members of halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxy or (10) 5 to 7membered heterocyclic having 1 to 3 nitrogen atoms, X is (1) hydrogen,(2) C₁₋₄ alkyl, (3) C₁₋₄ alkanoyl, (4) hydroxymethyl, (5) C₁₋₅alkanoyloxymethyl, (6) phenyl-C₁₋₄ alkyl which may be substituted by 1to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino,nitro or hydroxy, (7) phenyl which may be substituted by 1 to 3 membersof halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro orhydroxy, (8) C₁₋₄ alkoxycarbonyl, (9) phenyl-C₁₋₄ alkoxycarbonyl, (10)carbamoyl which may be substituted by 1 to 2 members of C₁₋₄ alkyl,phenyl or phenyl-C₁₋₄ alkyl or (11) carboxy, Y is ##STR74## in which R₅is (i) hydrogen, (ii) C₁₋₆ alkanoyl, (iii) phenyl-C₁₋₆ alkanoylunsubstituted or substituted by 1 to 3 members of halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxy, (iv) carbamoylunsubstituted or substituted by (1) C₁₋₄ alkyl, (2) phenyl unsubstitutedor substituted by 1 to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,methylenedioxy, amino, nitro or hydroxy or (3) phenyl-C₁₋₄ alkylunsubstituted or substituted by 1 to 3 members of halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxy, m is an integer of0 to 2 and n is an integer of 1 to 6,or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier, excipient ordiluent therefor.
 30. A method for treatment of ischemic cardiopathy,thrombosis, hypertension or cerebral circulatory disorder in a mammal,which comprises administering to said mammal an effective amount of acompound of the formula: ##STR75## wherein R₁ and R₂ are independentlyhydrogen, halogen, hydroxy, C₁₋₄ alkyl or C₁₋₄ alkoxy,R₃ and R₄ areindependently hydrogen, (i) C₁₋₄ alkyl which may be substituted by C₃₋₈cycloalkyl, halogen, hydroxy, C₁₋₄ alkoxy, C₁₋₅ alkanoyloxy, mono- ordi-C₁₋₄ alkylamino, C₃₋₈ cycloalkylamino, C₁₋₅ alkanoylamino, benzamido,C₁₋₄ alkylthio, carbamoyl, N-C₁₋₄ alkylcarbamoyl or N,N-di-C₁₋₄alkylcarbamoyl, (ii) C₃₋₈ cycloalkyl which may be substituted by C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₅ alkanoylamino or hydroxy, (iii) phenyl-C₁₋₄alkyl which may be substituted by 1 to 3 members of halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxy, or (iv) R₃ and R₄,taken together with the nitrogen atom, form (10) 5 to 7 membered ringwhich may be substituted by (1) C₁₋₄ alkyl, (2) phenyl unsubstituted orsubstituted by 1 to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,methylenedioxy, amino, nitro or hydroxy, (3) phenyl-C₁₋₄ alkylunsubstituted or substituted by 1 to 3 members of halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxy, (4) diphenyl-C₁₋₄alkyl unsubstituted or substituted by 1 to 3 members of halogen, C₁₋₄alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxy, (5)triphenyl-C₁₋₄ alkyl unsubstituted or substituted by 1 to 3 members ofhalogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro orhydroxy, (6) C₁₋₄ alkanoyl, (7) benzoyl unsubstituted or substituted by1 to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy,amino, nitro or hydroxy, (8) phenyl-C₁₋₄ alkanoyl unsubstituted orsubstituted by 1 to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,methylenedioxy, amino, nitro or hydroxy, (9) phenyl-C₁₋₄ alkenoylunsubstituted or substituted by 1 to 3 members of halogen, C₁₋₄ alkyl,C₁₋₄ alkoxy, methylenedioxy, amino, nitro or hydroxy or (10) 5 to 7membered heterocyclic having 1 to 3 nitrogen atoms, X is (1) hydrogen,(2) C₁₋₄ alkyl, (3) C₁₋₄ alkanoyl, (4) hydroxymethyl, (5) C₁₋₅alkanoyloxymethyl, (6) phenyl-C₁₋₄ alkyl which may be substituted by 1to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino,nitro or hydroxy, (7) phenyl which may be substituted by 1 to 3 membersof halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy, amino, nitro orhydroxy, (8) C₁₋₄ alkoxycarbonyl, (9) phenyl-C₁₋₄ alkoxycarbonyl,(10)carbamoyl which may be substituted by 1 to 2 members of C₁₋₄ alkyl,phenyl or phenyl-C₁₋₄ alkyl or (11) carboxy, ##STR76## which R₅ is (i)hydrogen, (ii) C₁₋₆ alkanoyl, (iii) phenyl-C₁₋₆ alkanoyl unsubstitutedor substituted by 1 to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,methylenedioxy, amino, nitro or hydroxy, (iv) carbamoyl unsubstituted orsubstituted by (1) C₁₋₄ alkyl, (2) phenyl unsubstituted or substitutedby 1 to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, methylenedioxy,amino, nitro or hydroxy or (3) phenyl-C₁₋₄ alkyl unsubstituted orsubstituted by 1 to 3 members of halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy,methylenedioxy, amino, nitro or hydroxy, m is an integer of 0 to 2 and nis an integer of 1 to 6,or a pharmaceutically acceptable salt thereof.31. A compound of the formula ##STR77## wherein R_(2') is hydroxy orC₁₋₄ alkoxy, and X is C₁₋₄ alkoxycarbonyl,or a pharmaceuticallyacceptable salt thereof.
 32. A compound according to claim 31, whereinthe group ##STR78## is 4-(4-hydroxyphenyl)piperazin-1-yl.
 33. A compoundaccording to claim 31, wherein X is methoxycarbonyl.
 34. A compoundaccording to claim 31, wherein R_(2') is C₁₋₄ alkoxy.
 35. A compoundaccording to claim 31, wherein R_(2') is methoxy.
 36. The compoundaccording to claim 31, which is methylcis-3-hydroxy-4-[3-[4-(4-hydroxyphenyl)piperazin-1-yl]propyl]-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.